bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–12–26
115 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Molecular Targets of Natural Compounds with Anti-Cancer Properties.
  2. Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path.
  3. Extracellular citrate and metabolic adaptations of cancer cells.
  4. Cancer metabolism and dietary interventions.
  5. Ketogenic Diets and their Therapeutic Potential on Breast Cancer: A Systemic Review.
  6. Dinner is served, sir: Fighting cancer with the right diet.
  7. Ferroptosis in Lung Cancer: From Molecular Mechanisms to Prognostic and Therapeutic Opportunities.
  8. Genetic Profiles of Ferroptosis in Malignant Brain Tumors and Off-Target Effects of Ferroptosis Induction.
  9. AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth.
  10. Past and Future Strategies to Inhibit Membrane Localization of the KRAS Oncogene.
  11. Enhanced Chemodynamic Therapy and Chemotherapy via Delivery of a Dual Threat ArtePt and Iodo-Click Reaction Mediated Glutathione Consumption.
  12. Targeting KRAS mutant lung cancer: light at the end of the tunnel.
  13. Current Photoactive Molecules for Targeted Therapy of Triple-Negative Breast Cancer.
  14. Protein acetylation effects on enzyme activity and metabolic pathway fluxes.
  15. A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity.
  16. Metabolic reprogramming in the arsenic carcinogenesis.
  17. Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment.
  18. Plant Derived Bioactive Compounds, Their Anti-Cancer Effects and In Silico Approaches as an Alternative Target Treatment Strategy for Breast Cancer: An Updated Overview.
  19. A comprehensive review on immuno-nanomedicine for breast cancer therapy: Technical challenges and troubleshooting measures.
  20. Camptothecin Encapsulated in β-Cyclodextrin-EDTA-Fe3O4 Nanoparticles Induce Metabolic Reprogramming Repair in HT29 Cancer Cells through Epigenetic Modulation: A Bioinformatics Approach.
  21. A review of the mechanisms of anti-cancer activities of some medicinal plants-biochemical perspectives.
  22. Ongoing and potential novel trends of pomegranate fruit peel; a comprehensive review of its health benefits and future perspectives as nutraceutical.
  23. Butyrate and Metformin Affect Energy Metabolism Independently of the Metabolic Phenotype in the Tumor Therapy Model.
  24. Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria.
  25. Synergistic Effect of Repolarization of M2 to M1 Macrophages Induced by Iron Oxide Nanoparticles Combined with Lactate Oxidase.
  26. Multifunctional nanoplatform based on g-C3N4, loaded with MnO2 and CuS nanoparticals for oxygen self-generation photodynamic/photothermal synergistic therapy.
  27. Quercetin attenuates the cardiotoxicity of doxorubicin-cyclophosphamide regimen and potentiates its chemotherapeutic effect against triple-negative breast cancer.
  28. Nanoparticles mediated target-specific drug delivery in prostate cancer: In-depth review.
  29. The emerging roles of nitric oxide in ferroptosis and pyroptosis of tumor cells.
  30. Current Landscape of Sonodynamic Therapy for Treating Cancer.
  31. Metformin Treatment or PRODH/POX-Knock out Similarly Induces Apoptosis by Reprograming of Amino Acid Metabolism, TCA, Urea Cycle and Pentose Phosphate Pathway in MCF-7 Breast Cancer Cells.
  32. Near-infrared light-triggered nano-prodrug for cancer gas therapy.
  33. Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy.
  34. Coordinating the mechanism of actions of ferroptosis and photothermal effect for cancer theranostics.
  35. Therapeutic Targets of KRAS in Colorectal Cancer.
  36. Immune Effect of Active Components of Traditional Chinese Medicine on Triple-Negative Breast Cancer.
  37. Smart Nano-PROTACs Reprogram Tumor Microenvironment for Activatable Photo-metabolic Cancer Immunotherapy.
  38. Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin.
  39. Potentiating the Cytotoxic Activity of a Novel Simvastatin-Loaded Cubosome against Breast Cancer Cells: Insights on Dual Cell Death via Ferroptosis and Apoptosis.
  40. Health Benefits and Pharmacological Properties of Carvone.
  41. Breast Cancer Cell Subtypes Display Different Metabolic Phenotypes That Correlate with Their Clinical Classification.
  42. Emerging Biomaterials-Based Strategies for Inhibiting Vasculature Function in Cancer Therapy.
  43. The Regulatory Effects and the Signaling Pathways of Natural Bioactive Compounds on Ferroptosis.
  44. Synergistic effects of metformin and curcumin on cytotoxicity of chemotherapy drugs using a gastric cancer cell line model.
  45. Photodynamic and Photothermal Therapy of Hepatocellular Carcinoma.
  46. Innovative Approaches of Engineering Tumor-Targeting Bacteria with Different Therapeutic Payloads to Fight Cancer: A Smart Strategy of Disease Management.
  47. Medicinal Plants for Glioblastoma Treatment.
  48. Metabolic Pathways and Targets in Chondrosarcoma.
  49. PKM2 Is the Target of a Multi-Herb-Combined Decoction During the Inhibition of Gastric Cancer Progression.
  50. PEGylated Liposomal Encapsulation Improves the Antitumor Efficacy of Combretastatin A4 in Murine 4T1 Triple-Negative Breast Cancer Model.
  51. Recent Advances and Trends in Nanoparticles based Photothermal and Photodynamic Therapy.
  52. Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs.
  53. The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells.
  54. Mitochondria-targeted nanoplatforms for enhanced photodynamic therapy against hypoxia tumor.
  55. Dietary Phytoestrogens and Their Metabolites as Epigenetic Modulators with Impact on Human Health.
  56. Resveratrol-Loaded TPGS-Resveratrol-Solid Lipid Nanoparticles for Multidrug-Resistant Therapy of Breast Cancer: In Vivo and In Vitro Study.
  57. Dual-Responsive and ROS-Augmented Nanoplatform for Chemo/Photodynamic/Chemodynamic Combination Therapy of Triple Negative Breast Cancer.
  58. The emerging role of selenium metabolic pathways in cancer: New therapeutic targets for cancer.
  59. Targeted regulation of autophagy using nanoparticles: New insight into cancer therapy.
  60. Chiral Cu2-xSe Nanoparticles for Enhanced Synergistic Cancer Chemodynamic/Photothermal Therapy in the Second Near-Infrared Biowindow.
  61. Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance.
  62. Targeting KRAS in NSCLC: Old Failures and New Options for "Non-G12c" Patients.
  63. Apigenin Induces Autophagy and Cell Death by Targeting EZH2 under Hypoxia Conditions in Gastric Cancer Cells.
  64. Dihydroartemisinin enhances the inhibitory effect of sorafenib on HepG2 cells by inducing ferroptosis and inhibiting energy metabolism.
  65. Trimethyl chitosan coated palladium nanoparticles as a photothermal agent and its in vitro evaluation in 2D and 3D model of breast cancer cells.
  66. Polyphenols as Antioxidants for Extending Food Shelf-Life and in the Prevention of Health Diseases: Encapsulation and Interfacial Phenomena.
  67. Murburn precepts for lactic-acidosis, Cori cycle, and Warburg effect: Interactive dynamics of dehydrogenases, protons, and oxygen.
  68. Molecular Effectors of Photodynamic Therapy-Mediated Resistance to Cancer Cells.
  69. Sempervirine Inhibits Proliferation and Promotes Apoptosis by Regulating Wnt/β-Catenin Pathway in Human Hepatocellular Carcinoma.
  70. Polylactide Nanoparticles Encapsulating Indocyanine Green for Photothermal Therapy of Prostate Cancer Cells.
  71. Why may citrate sodium significantly increase the effectiveness of transarterial chemoembolization in hepatocellular carcinoma?
  72. Controlled temperature-mediated curcumin release from magneto-thermal nanocarriers to kill bone tumors.
  73. Ferroptosis in Non-Small Cell Lung Cancer: Progression and Therapeutic Potential on It.
  74. Role of photobleaching process of indocyanine green for killing neuroblastoma cells.
  75. Biocompatible BSA-Ag2S nanoparticles for photothermal therapy of cancer.
  76. Multi-ligand modified PC@DOX-PA/EGCG micelles effectively inhibit the growth of ER+, PR+ or HER2+ breast cancer.
  77. Engineering Oxygen-Irrelevant Radical Nanogenerator for Hypoxia-Independent Magnetothermodynamic Tumor Nanotherapy.
  78. Insight into the Double-Edged Role of Ferroptosis in Disease.
  79. Nutraceuticals and Herbal Food Supplements for Weight Loss: Is There a Prebiotic Role in the Mechanism of Action?
  80. The potential role of vitamin C in empowering cancer immunotherapy.
  81. Starring role of Biomarkers and Anticancer Agents as a Major Driver in Precision Medicine of Cancer Therapy.
  82. Nanofactory for metabolic and chemodynamic therapy: pro-tumor lactate trapping and anti-tumor ROS transition.
  83. A pH-responsive complex based on supramolecular organic framework for drug-resistant breast cancer therapy.
  84. Platinum and Taxane Based Adjuvant and Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: A Narrative Review.
  85. An Efficient Carbon-Based Drug Delivery System for Cancer Therapy through the Nucleus Targeting and Mitochondria Mediated Apoptotic Pathway.
  86. Cancer vaccines as a targeted immunotherapy approach for breast cancer: an update of clinical evidence.
  87. An update of advanced nanoplatforms for Glioblastoma Multiforme Management.
  88. Novel Perspectives towards RNA-Based Nano-Theranostic Approaches for Cancer Management.
  89. Superfruits in China: Bioactive phytochemicals and their potential health benefits - A Review.
  90. Identification of Pyruvate Carboxylase as the Cellular Target of Natural Bibenzyls with Potent Anticancer Activity against Hepatocellular Carcinoma via Metabolic Reprogramming.
  91. Kinetics of Nanomedicine in Tumor Spheroid as an In Vitro Model System for Efficient Tumor-Targeted Drug Delivery With Insights From Mathematical Models.
  92. Traditional Chinese medicine for precancerous lesions of gastric cancer: A review.
  93. Functional precision oncology: Testing tumors with drugs to identify vulnerabilities and novel combinations.
  94. A multifunctional study of naturally occurring pyrazines in biological systems; formation mechanisms, metabolism, food applications and functional properties.
  95. A vibrational in vitro approach to evaluate the potential of monoolein nanoparticles as isofuranodiene carrier in MDA-MB 231 breast cancer cell line: New insights from Infrared and Raman microspectroscopies.
  96. Aflatoxin B1: metabolism, toxicology, and its involvement in oxidative stress and cancer development.
  97. The Potential Role of Curcumin in Modulating the Master Antioxidant Pathway in Diabetic Hypoxia-Induced Complications.
  98. A molybdenum oxide-based degradable nanosheet for combined chemo-photothermal therapy to improve tumor immunosuppression and suppress distant tumors and lung metastases.
  99. LC-MS/HRMS Analysis, Anti-Cancer, Anti-Enzymatic and Anti-Oxidant Effects of Boerhavia diffusa Extracts: A Potential Raw Material for Functional Applications.
  100. Synthesis of Photo, Oxidative, and Reductive Triple-Stimuli-Responsive Block Copolymer Micelles as Nanocarriers for Controlled Release.
  101. Curcumin Nanoparticles Inhibiting Ferroptosis for the Enhanced Treatment of Intracerebral Hemorrhage.
  102. Carbon Dots with Intrinsic Bioactivities for Photothermal Optical Coherence Tomography, tumor-specific Therapy and Postoperative Wound Management.
  103. Liriopogons (Genera Ophiopogon and Liriope, Asparagaceae): A Critical Review of the Phytochemical and Pharmacological Research.
  104. Methods for monitoring cancer cell pyroptosis.
  105. The Role of Vitamin C in Cancer Prevention and Therapy: A Literature Review.
  106. Z-Scheme heterostructures for glucose oxidase-sensitized radiocatalysis and starvation therapy of tumors.
  107. Potential Natural Compounds for the Prevention and Treatment of Nonalcoholic Fatty Liver Disease: A Review on Molecular Mechanisms.
  108. Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer.
  109. Diet Impact on Obesity beyond Calories and Trefoil Factor Family 2 (TFF2) as an Illustration: Metabolic Implications and Potential Applications.
  110. Tumor Microcalcification-mediated Relay Drug Delivery for Photodynamic Immunotherapy of Breast Cancer.
  111. Natural Peptides Inducing Cancer Cell Death: Mechanisms and Properties of Specific Candidates for Cancer Therapeutics.
  112. A Mitochondrial Oxidative Stress Amplifier to Overcome Hypoxia Resistance for Enhanced Photodynamic Therapy.
  113. Energy balance-related factors and risk of colorectal cancer expressing different levels of proteins involved in the Warburg-effect.
  114. Drug repositioning: Using psychotropic drugs for the treatment of glioma.
  115. Carbon Ion Radiotherapy Evokes a Metabolic Reprogramming and Individualized Response in Prostate Cancer.
  1. Int J Mol Sci. 2021 Dec 20. pii: 13659. [Epub ahead of print]22(24):
    Molecular Targets of Natural Compounds with Anti-Cancer Properties.
    Małgorzata Kubczak, Aleksandra Szustka, Małgorzata Rogalińska.
      Cancer is the second leading cause of death in humans. Despite rapid developments in diagnostic methods and therapies, metastasis and resistance to administrated drugs are the main obstacles to successful treatment. Therefore, the main challenge should be the diagnosis and design of optimal therapeutic strategies for patients to increase their chances of responding positively to treatment and increase their life expectancy. In many types of cancer, a deregulation of multiple pathways has been found. This includes disturbances in cellular metabolism, cell cycle, apoptosis, angiogenesis, or epigenetic modifications. Additionally, signals received from the microenvironment may significantly contribute to cancer development. Chemical agents obtained from natural sources seem to be very attractive alternatives to synthetic compounds. They can exhibit similar anti-cancer potential, usually with reduced side effects. It was reported that natural compounds obtained from fruits and vegetables, e.g., polyphenols, flavonoids, stilbenes, carotenoids and acetogenins, might be effective against cancer cells in vitro and in vivo. Several published results indicate the activity of natural compounds on protein expression by its influence on transcription factors. They could also be involved in alterations in cellular response, cell signaling and epigenetic modifications. Such natural components could be used in our diet for anti-cancer protection. In this review, the activities of natural compounds, including anti-cancer properties, are described. The influence of natural agents on cancer cell metabolism, proliferation, signal transduction and epigenetic modifications is highlighted.
    Keywords:  curcumin; graviola; lycopene; natural anti-cancer agents; quercetin; resveratrol
    DOI:  https://doi.org/10.3390/ijms222413659
  2. Biomedicines. 2021 Dec 18. pii: 1942. [Epub ahead of print]9(12):
    Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path.
    Elisabetta Iessi, Rosa Vona, Camilla Cittadini, Paola Matarrese.
      In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by both unfavorable environmental conditions and therapeutic drugs. Many oncogenes and tumor suppressor genes have a significant effect on cellular metabolism, as there is a close relationship between the pathways activated by these genes and the various metabolic options. The metabolic adaptations observed in cancer cells not only promote their proliferation and invasion, but also their survival by inducing intrinsic and acquired resistance to various anticancer agents and to various forms of cell death, such as apoptosis, necroptosis, autophagy, and ferroptosis. In this review we analyze the main metabolic differences between cancer and non-cancer cells and how these can affect the various cell death pathways, effectively determining the susceptibility of cancer cells to therapy-induced death. Targeting the metabolic peculiarities of cancer could represent in the near future an innovative therapeutic strategy for the treatment of those tumors whose metabolic characteristics are known.
    Keywords:  OXPHOS; acidity; anticancer therapy; cancer cell metabolism; cell death; chemoresistance; glucose; glycolysis; oxidative metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines9121942
  3. Cancer Metastasis Rev. 2021 Dec 21.
    Extracellular citrate and metabolic adaptations of cancer cells.
    E Kenneth Parkinson, Jerzy Adamski, Grit Zahn, Andreas Gaumann, Fabian Flores-Borja, Christine Ziegler, Maria E Mycielska.
      It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.
    Keywords:  Cancer-associated cells; Citrate; OXPHOS; Redox; Senescence; Warburg effect
    DOI:  https://doi.org/10.1007/s10555-021-10007-1
  4. Cancer Biol Med. 2021 Dec 22. pii: j.issn.2095-3941.2021.0461. [Epub ahead of print]
    Cancer metabolism and dietary interventions.
    Lin Qian, Fan Zhang, Miao Yin, Qunying Lei.
      Metabolic remodeling is a key feature of cancer development. Knowledge of cancer metabolism has greatly expanded since the first observation of abnormal metabolism in cancer cells, the so-called Warburg effect. Malignant cells tend to modify cellular metabolism to favor specialized fermentation over the aerobic respiration usually used by most normal cells. Thus, targeted cancer therapies based on reprogramming nutrient or metabolite metabolism have received substantial attention both conceptually and in clinical practice. In particular, the management of nutrient availability is becoming more attractive in cancer treatment. In this review, we discuss recent findings on tumor metabolism and potential dietary interventions based on the specific characteristics of tumor metabolism. First, we present a comprehensive overview of changes in macronutrient metabolism. Carbohydrates, amino acids, and lipids, are rewired in the cancer microenvironment individually or systematically. Second, we summarize recent progress in cancer interventions applying different types of diets and specific nutrient restrictions in pre-clinical research or clinical trials.
    Keywords:  Cancer metabolism; amino acid; carbohydrate; diet intervention; lipid
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0461
  5. Cancer Manag Res. 2021 ;13 9147-9155
    Ketogenic Diets and their Therapeutic Potential on Breast Cancer: A Systemic Review.
    Mohammed Jemal, Tewodros Shibabaw Molla, Tadesse Asmamaw Dejenie.
      Breast cancer remains a major cause of morbidity and mortality in women, and there is still a lack of complementary approaches to significantly improve the efficacy of standard therapies. For many kinds of cancers, the usual standard care is the combination of surgery, radiation, and chemotherapy. However, this standard therapy is not effective alone. Therefore, new approaches that increase therapeutic effectiveness are urgently needed. The ketogenic diet is a novel therapeutic approach for certain types of cancers, as indicated by several preclinical and clinical evidences. The ketogenic diet, which consists of a high-fat, low-carbohydrate diet with adequate protein, appears to sensitize most cancers to standard therapy by utilizing the reprogrammed metabolism of cancer cells, making it a promising candidate for adjuvant cancer treatment. The majority of preclinical and clinical studies argue that the use of a ketogenic diet in combination with standard therapies is based on its potential to improve the antitumor effects of conventional chemotherapy, its overall good safety and tolerability, and quality of life improvement. According to new evidence, a ketogenic diet lowers the level of glucose and insulin in the blood, which are necessary for tumor growth. Thus, the ketogenic diet has emerged as a potential treatment option for a variety of cancers, including breast cancer. Besides, implementation of a Ketogenic diet in the clinic could improve progression-free and overall survival for patients with breast cancer. This review summarizes the composition and metabolism of ketogenic diets and their potential mechanisms in breast carcinogenesis in addition to their therapeutic potential on breast cancer.
    Keywords:  adjuvant breast cancer therapy; breast cancer; ketogenic diet
    DOI:  https://doi.org/10.2147/CMAR.S339970
  6. Cell. 2021 Dec 22. pii: S0092-8674(21)01386-6. [Epub ahead of print]184(26): 6226-6228
    Dinner is served, sir: Fighting cancer with the right diet.
    Andrés Méndez-Lucas, Mariia Yuneva.
      Altered metabolism of tumors offers an opportunity to use metabolic interventions as a therapeutic strategy. Lien et al. demonstrate that understanding how specific diets with different carbohydrate and fat composition affect tumor metabolism is essential in order to use this opportunity efficiently.
    DOI:  https://doi.org/10.1016/j.cell.2021.11.036
  7. Front Oncol. 2021 ;11 792827
    Ferroptosis in Lung Cancer: From Molecular Mechanisms to Prognostic and Therapeutic Opportunities.
    Peyman Tabnak, Zanyar HajiEsmailPoor, Soroush Soraneh.
      Lung cancer is the second commonly diagnosed malignancy worldwide and has the highest mortality rate among all cancers. Tremendous efforts have been made to develop novel strategies against lung cancer; however, the overall survival of patients still is low. Uncovering underlying molecular mechanisms of this disease can open up new horizons for its treatment. Ferroptosis is a newly discovered type of programmed cell death that, in an iron-dependent manner, peroxidizes unsaturated phospholipids and results in the accumulation of radical oxygen species. Subsequent oxidative damage caused by ferroptosis contributes to cell death in tumor cells. Therefore, understanding its molecular mechanisms in lung cancer appears as a promising strategy to induce ferroptosis selectively. According to evidence published up to now, significant numbers of research have been done to identify ferroptosis regulators in lung cancer. Therefore, this review aims to provide a comprehensive standpoint of molecular mechanisms of ferroptosis in lung cancer and address these molecules' prognostic and therapeutic values, hoping that the road for future studies in this field will be paved more efficiently.
    Keywords:  Nrf2; ROS; biomarkers; cell death; ferroptosis; immunity; iron metabolism; lung cancer
    DOI:  https://doi.org/10.3389/fonc.2021.792827
  8. Front Oncol. 2021 ;11 783067
    Genetic Profiles of Ferroptosis in Malignant Brain Tumors and Off-Target Effects of Ferroptosis Induction.
    Marc Dahlmanns, Eduard Yakubov, Jana Katharina Dahlmanns.
      Glioblastoma represents the most devastating form of human brain cancer, associated with a very poor survival rate of patients. Unfortunately, treatment options are currently limited and the gold standard pharmacological treatment with the chemotherapeutic drug temozolomide only slightly increases the survival rate. Experimental studies have shown that the efficiency of temozolomide can be improved by inducing ferroptosis - a recently discovered form of cell death, which is different from apoptosis, necrosis, or necroptosis and, which is characterized by lipid peroxidation and reactive oxygen species accumulation. Ferroptosis can also be activated to improve treatment of malignant stages of neuroblastoma, meningioma, and glioma. Due to their role in cancer treatment, ferroptosis-gene signatures have recently been evaluated for their ability to predict survival of patients. Despite positive effects during chemotherapy, the drugs used to induce ferroptosis - such as erastin and sorafenib - as well as genetic manipulation of key players in ferroptosis - such as the cystine-glutamate exchanger xCT and the glutathione peroxidase GPx4 - also impact neuronal function and cognitive capabilities. In this review, we give an update on ferroptosis in different brain tumors and summarize the impact of ferroptosis on healthy tissues.
    Keywords:  brain tumor therapy; erastin; ferroptosis; glioblastoma; neuroblastoma; neuron; off-target effects; xCT
    DOI:  https://doi.org/10.3389/fonc.2021.783067
  9. Metabolites. 2021 Nov 29. pii: 811. [Epub ahead of print]11(12):
    AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth.
    Xunzhe Yin, Wenbo Li, Jiaxin Zhang, Wenjing Zhao, Huaxing Cai, Chi Zhang, Zuojia Liu, Yan Guo, Jin Wang.
      Targeting cancer cell metabolism has been an attractive approach for cancer treatment. However, the role of metabolic alternation in cancer is still unknown whether it functions as a tumor promoter or suppressor. Applying the cancer gene-metabolism integrative network model, we predict adenosine monophosphate-activated protein kinase (AMPK) to function as a central hub of metabolic landscape switching in specific liver cancer subtypes. For the first time, we demonstrate that the phytochemical levo-tetrahydropalmatine (l-THP), a Corydalis yanhusuo-derived clinical drug, as an AMPK activator via autophagy-mediated metabolic switching could kill the hepatocellular carcinoma HepG2 cells. Mechanistically, l-THP promotes the autophagic response by activating the AMPK-mTOR-ULK1 and the ROS-JNK-ATG cascades and impairing the ERK/AKT signaling. All these processes ultimately synergize to induce the decreased mitochondrial oxidative phosphorylation (OXPHOS) and mitochondrial damage. Notably, silencing AMPK significantly inhibits the autophagic flux and recovers the decreased OXPHOS metabolism, which results in HepG2 resistance to l-THP treatment. More importantly, l-THP potently reduces the growth of xenograft HepG2 tumor in nude mice without affecting other organs. From this perspective, our findings support the conclusion that metabolic change is an alternative approach to influence the development of HCC.
    Keywords:  AMPK; autophagy; cancer metabolism; hepatocellular carcinoma; levo-tetrahydropalmatine
    DOI:  https://doi.org/10.3390/metabo11120811
  10. Int J Mol Sci. 2021 Dec 07. pii: 13193. [Epub ahead of print]22(24):
    Past and Future Strategies to Inhibit Membrane Localization of the KRAS Oncogene.
    Malak Haidar, Patrick Jacquemin.
      KRAS is one of the most studied oncogenes. It is well known that KRAS undergoes post-translational modifications at its C-terminal end. These modifications are essential for its membrane location and activity. Despite significant efforts made in the past three decades to target the mechanisms involved in its membrane localization, no therapies have been approved and taken into the clinic. However, many studies have recently reintroduced interest in the development of KRAS inhibitors, either by directly targeting KRAS or indirectly through the inhibition of critical steps involved in post-translational KRAS modifications. In this review, we summarize the approaches that have been applied over the years to inhibit the membrane localization of KRAS in cancer and propose a new anti-KRAS strategy that could be used in clinic.
    Keywords:  KRAS; RAS; cancer; plasma membrane
    DOI:  https://doi.org/10.3390/ijms222413193
  11. Small Methods. 2021 Dec;5(12): e2101047
    Enhanced Chemodynamic Therapy and Chemotherapy via Delivery of a Dual Threat ArtePt and Iodo-Click Reaction Mediated Glutathione Consumption.
    Qiao Jin, Siqi Yan, Hao Hu, Long Jin, Yuliang Pan, Jun Zhang, Jia Huang, Haihua Xiao, Peiguo Cao.
      Cisplatin has been used as standard regimen for hepatocellular carcinoma (HCC), but its therapeutic efficacy is greatly limited by the drug resistance. Cisplatin alone cannot achieve an ideal therapeutic outcome. Herein, a dual threat hybrid artemisinin platinum (ArtePt) is synthesized to combine chemodynamic therapy (CDT) with chemotherapy. On the one hand, artesunate can react with intracellular ferrous ion to generate reactive oxygen species (ROS) via Fenton reaction for CDT. On the other hand, cisplatin can target DNA for chemotherapy. However, GSH in cancer cells can effectively consume free radicals and detoxify cisplatin simultaneously, which compromised the efficacy of CDT and chemotherapy. Hence, an amphiphilic polymer with an iodine atom in the side chain is designed and encapsulated ArtePt to form NP(ArtePt). This iodine containing polymer NP(ArtePt) can effectively deplete intracellular GSH via an Iodo-Click reaction, thereby enhancing the effect of CDT as well as chemotherapy. Thereafter, a patient-derived xenograft model of hepatic carcinoma (PDXHCC ) is established to evaluate the therapeutic effect of NP(ArtePt), and a significant antitumor effect is achieved with NP(ArtePt). Overall, this study provides an effective strategy to combine CDT with chemotherapy to enhance the efficacy of cisplatin via Iodo-Click reaction, opening a new avenue for the cancer treatment.
    Keywords:  GSH consumption; chemodynamic therapy (CDT); chemotherapy; cisplatin; click reactions
    DOI:  https://doi.org/10.1002/smtd.202101047
  12. Mol Oncol. 2021 Dec 23.
    Targeting KRAS mutant lung cancer: light at the end of the tunnel.
    Matthias Drosten, Mariano Barbacid.
      For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRASG12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the MAPK pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.
    Keywords:  KRASG12C inhibitors; Lung adenocarcinoma; RAF1; RAS signaling; genetically engineered mouse tumor models; tumor resistance
    DOI:  https://doi.org/10.1002/1878-0261.13168
  13. Molecules. 2021 Dec 17. pii: 7654. [Epub ahead of print]26(24):
    Current Photoactive Molecules for Targeted Therapy of Triple-Negative Breast Cancer.
    Cristina J Dias, Luisa Helguero, Maria Amparo F Faustino.
      Cancer is the second leading cause of death worldwide; therefore, there is an urgent need to find safe and effective therapies. Triple-negative breast cancer (TNBC) is diagnosed in ca. 15-20% of BC and is extremely aggressive resulting in reduced survival rate, which is mainly due to the low therapeutic efficacy of available treatments. Photodynamic therapy (PDT) is an interesting therapeutic approach in the treatment of cancer; the photosensitizers with good absorption in the therapeutic window, combined with their specific targeting of cancer cells, have received particular interest. This review aims to revisit the latest developments on chlorin-based photoactive molecules for targeted therapy in TNBC. Photodynamic therapy, alone or combined with other therapies (such as chemotherapy or photothermal therapy), has potential to be a safe and a promising approach against TNBC.
    Keywords:  TNBC; breast cancer; chemotherapy chlorin-based molecules; photodynamic therapy; photothermal therapy; triple-negative
    DOI:  https://doi.org/10.3390/molecules26247654
  14. J Cell Biochem. 2021 Dec 20.
    Protein acetylation effects on enzyme activity and metabolic pathway fluxes.
    Álvaro Marín-Hernández, José S Rodríguez-Zavala, Ricardo Jasso-Chávez, Emma Saavedra, Rafael Moreno-Sánchez.
      Acetylation of proteins seems a widespread process found in the three domains of life. Several studies have shown that besides histones, acetylation of lysine residues also occurs in non-nuclear proteins. Hence, it has been suggested that this covalent modification is a mechanism that might regulate diverse metabolic pathways by modulating enzyme activity, stability, and/or subcellular localization or interaction with other proteins. However, protein acetylation levels seem to have low correlation with modification of enzyme activity and pathway fluxes. In addition, the results obtained with mutant enzymes that presumably mimic acetylation have frequently been over-interpreted. Moreover, there is a generalized lack of rigorous enzyme kinetic analysis in parallel to acetylation level determinations. The purpose of this review is to analyze the current findings on the impact of acetylation on metabolic enzymes and its repercussion on metabolic pathways function/regulation.
    Keywords:  Krebs cycle; covalent regulation; energy metabolism; enzyme kinetics; glycolysis; modeling
    DOI:  https://doi.org/10.1002/jcb.30197
  15. J Nanobiotechnology. 2021 Dec 20. 19(1): 441
    A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity.
    Yawei Li, Qing Pei, Baiji Cui, Hongmei Zhang, Liu Han, Wenqing Li, Wenhe Zhu, Xianmin Feng, Zhigang Xie.
      Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA2-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug.
    Keywords:  Antitumor activity; Dihydroartemisinin; Dimeric nanoprodrug; PI3K/AKT/HIF-1α signaling pathway; Redox-responsive
    DOI:  https://doi.org/10.1186/s12951-021-01200-z
  16. Ecotoxicol Environ Saf. 2021 Dec 21. pii: S0147-6513(21)01210-0. [Epub ahead of print]229 113098
    Metabolic reprogramming in the arsenic carcinogenesis.
    Yihui Ruan, Xin Fang, Tingyue Guo, Yiting Liu, Yu Hu, Xuening Wang, Yuxin Hu, Lanyue Gao, Yongfang Li, Jingbo Pi, Yuanyuan Xu.
      Chronic exposure to arsenic has been associated with a variety of cancers with the mechanisms undefined. Arsenic exposure causes alterations in metabolites in bio-samples. Recent research progress on cancer biology suggests that metabolic reprogramming contributes to tumorigenesis. Therefore, metabolic reprogramming provides a new clue for the mechanisms of arsenic carcinogenesis. In the present manuscript, we review the latest findings in reprogramming of glucose, lipids, and amino acids in response to arsenic exposure. Most studies focused on glucose reprogramming and found that arsenic exposure enhanced glycolysis. However, in vivo studies observed "reverse Warburg effect" in some cases due to the complexity of the disease evolution and microenvironment. Arsenic exposure has been reported to disturb lipid deposition by inhibiting lipolysis, and induce serine-glycine one-carbon pathway. As a dominant mechanism for arsenic toxicity, oxidative stress is considered to link with metabolism reprogramming. Few studies analyzed the causal relationship between metabolic reprogramming and arsenic-induced cancers. Metabolic alterations may vary with exposure doses and periods. Identifying metabolic alterations common among humans and experiment models with human-relevant exposure characteristics may guide future investigations.
    Keywords:  Amino acid metabolism; Arsenic; Carcinogenic mechanism; Glucose metabolism; Lipid metabolism; Oxidative stress
    DOI:  https://doi.org/10.1016/j.ecoenv.2021.113098
  17. Int J Mol Sci. 2021 Dec 17. pii: 13571. [Epub ahead of print]22(24):
    Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment.
    Tai-Na Wu, Hui-Ming Chen, Lie-Fen Shyur.
      Triple-negative breast cancer (TNBC) is defined based on the absence of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. Currently, chemotherapy is the major therapeutic approach for TNBC patients; however, poor prognosis after a standard chemotherapy regimen is still commonplace due to drug resistance. Abnormal tumor metabolism and infiltrated immune or stromal cells in the tumor microenvironment (TME) may orchestrate mammary tumor growth and metastasis or give rise to new subsets of cancer cells resistant to drug treatment. The immunosuppressive mechanisms established in the TME make cancer cell clones invulnerable to immune recognition and killing, and turn immune cells into tumor-supporting cells, hence allowing cancer growth and dissemination. Phytochemicals with the potential to change the tumor metabolism or reprogram the TME may provide opportunities to suppress cancer metastasis and/or overcome chemoresistance. Furthermore, phytochemical intervention that reprograms the TME away from favoring immunoevasion and instead towards immunosurveillance may prevent TNBC metastasis and help improve the efficacy of combination therapies as phyto-adjuvants to combat drug-resistant TNBC. In this review, we summarize current findings on selected bioactive plant-derived natural products in preclinical mouse models and/or clinical trials with focus on their immunomodulatory mechanisms in the TME and their roles in regulating tumor metabolism for TNBC prevention or therapy.
    Keywords:  drug resistance; metabolism; metastasis; phyto-adjuvants; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms222413571
  18. Cancers (Basel). 2021 Dec 10. pii: 6222. [Epub ahead of print]13(24):
    Plant Derived Bioactive Compounds, Their Anti-Cancer Effects and In Silico Approaches as an Alternative Target Treatment Strategy for Breast Cancer: An Updated Overview.
    Vijayakumar Shrihastini, Pandiyan Muthuramalingam, Sivakumar Adarshan, Mariappan Sujitha, Jen-Tsung Chen, Hyunsuk Shin, Manikandan Ramesh.
      Cancer is one of the most common malignant diseases that occur worldwide, among which breast cancer is the second leading cause of death in women. The subtypes are associated with differences in the outcome and were selected for treatments according to the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor. Triple-negative breast cancer, one of the subtypes of breast cancer, is difficult to treat and can even lead to death. If breast cancer is not treated during the initial stages, it may spread to nearby organs, a process called metastasis, through the blood or lymph system. For in vitro studies, MCF-7, MDA-MB-231, MDA-MB-468, and T47B are the most commonly used breast cancer cell lines. Clinically, chemotherapy and radiotherapy are usually expensive and can also cause side effects. To overcome these issues, medicinal plants could be the best alternative for chemotherapeutic drugs with fewer side effects and cost-effectiveness. Furthermore, the genes involved in breast cancer can be regulated and synergized with signaling molecules to suppress the proliferation of breast cancer cells. In addition, nanoparticles encapsulating (nano-encapsulation) medicinal plant extracts showed a significant reduction in the apoptotic and cytotoxic activities of breast cancer cells. This present review mainly speculates an overview of the native medicinal plant derived anti-cancerous compounds with its efficiency, types and pathways involved in breast cancer along with its genes, the mechanism of breast cancer brain metastasis, chemoresistivity and its mechanism, bioinformatics approaches which could be an effective alternative for drug discovery.
    Keywords:  bioinformatics; breast cancer; medicinal plants; metastasis; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cancers13246222
  19. Int Immunopharmacol. 2021 Dec 16. pii: S1567-5769(21)01069-9. [Epub ahead of print]103 108433
    A comprehensive review on immuno-nanomedicine for breast cancer therapy: Technical challenges and troubleshooting measures.
    Kandasamy Saravanakumar, Sathiyaseelan Anbazhagan, Janandi Pujani Usliyanage, Kumar Vishven Naveen, Udari Wijesinghe, Hu Xiaowen, Veeraraghavan Vishnu Priya, Gobika Thiripuranathar, Myeong-Hyeon Wang.
      Nanosized drug carriers have received a major attention in cancer therapeutics and theranostics. The immuno-nanomedicine is a combination of monoclonal antibody (mAb)/mAb-drug-nanoparticles. The immuno-nanomedicine offers a promising strategy to target cancer cells. However, the understating of nanotechnology, cancer biology, immunomedicine, and nanoparticle surface chemistry has provided a better clue to prepare the effective immuno-nanomedicine for cancer therapy. Moreover, the selection of nanoparticles type and its composition is essential for development of efficient drug delivery system (DDS) to target the cancer cell site. Immuno-nanomedicine works in the ligand-receptor binding mechanism through the interaction of mAb conjugated nanoparticles and specific antigen over expressed on target cancer cells. Therefore, the selection of specific receptors in the cancer cell and their ligand is important to prepare the active immuno-nanomedicines. Moreover, the factors such as drug loading, entrapment efficiency, size, shape, and ligand conjugation of a nanocarrier are considered as major factors for a better cancer cell, internalization, drug release, and cancer cell ablation. The target-based over-expression of antigen, mAb is engineered and conjugated with nanoparticles for successful targeting of the cancer cells without causing adverse effects to normal cells. Therefore, this review analyzed the fundamental factors in the immuno-nanomedicine for breast cancer and its technical challenges in the fabrication of the antibody alone/and drug conjugated nanoparticles.
    Keywords:  Antibody; Antibody-drug conjugate; Cancer therapy; Nanocarrier; Nanomedicine
    DOI:  https://doi.org/10.1016/j.intimp.2021.108433
  20. Nanomaterials (Basel). 2021 Nov 23. pii: 3163. [Epub ahead of print]11(12):
    Camptothecin Encapsulated in β-Cyclodextrin-EDTA-Fe3O4 Nanoparticles Induce Metabolic Reprogramming Repair in HT29 Cancer Cells through Epigenetic Modulation: A Bioinformatics Approach.
    Aisha Farhana, Avin Ee-Hwan Koh, Pooi Ling Mok, Abdullah Alsrhani, Yusuf Saleem Khan, Suresh Kumar Subbiah.
      Cancer progresses through a distinctive reprogramming of metabolic pathways directed by genetic and epigenetic modifications. The hardwired changes induced by genetic mutations are resilient, while epigenetic modifications are softwired and more vulnerable to therapeutic intervention. Colon cancer is no different. This gives us the need to explore the mechanism as an attractive therapeutic target to combat colon cancer cells. We have previously established the enhanced therapeutic efficacy of a newly formulated camptothecin encapsulated in β-cyclodextrin-EDTA-Fe3O4 nanoparticles (CPT-CEF) in colon cancer cells. We furthered this study by carrying out RNA sequencing (RNA-seq) to underscore specific regulatory signatures in the CPT-CEF treated versus untreated HT29 cells. In the study, we identified 95 upregulated and 146 downregulated genes spanning cellular components and molecular and metabolic functions. We carried out extensive bioinformatics analysis to harness genes potentially involved in epigenetic modulation as either the cause or effect of metabolic rewiring exerted by CPT-CEF. Significant downregulation of 13 genes involved in the epigenetic modulation and 40 genes from core metabolism was identified. Three genes, namely, DNMT-1, POLE3, and PKM-2, were identified as the regulatory overlap between epigenetic drivers and metabolic reprogramming in HT29 cells. Based on our results, we propose a possible mechanism that intercepts the two functional axes, namely epigenetic control, and metabolic modulation via CPT-CEF in colon cancer cells, which could skew cancer-induced metabolic deregulation towards metabolic repair. Thus, the study provides avenues for further validation of transcriptomic changes affected by these deregulated genes at epigenetic level, and ultimately may be harnessed as targets for regenerating normal metabolism in colon cancer with better treatment potential, thereby providing new avenues for colon cancer therapy.
    Keywords:  colon cancer; epigenetic modulation; metabolic reprogramming; nanoparticles; transcriptome analysis
    DOI:  https://doi.org/10.3390/nano11123163
  21. J Basic Clin Physiol Pharmacol. 2021 Dec 16.
    A review of the mechanisms of anti-cancer activities of some medicinal plants-biochemical perspectives.
    Patrick E Aba, John I Ihedioha, Isaac U Asuzu.
      Cancer is a disease resulting in unbridled growth of cells due to dysregulation in the balance of cell populations. Various management procedures in handling cases of cancer are not without their adverse side effects on the normal cells. Medicinal plants/herbs have been in use in the management of various ailments, including cancer, for a long time. Medicinal plants have been credited with wide safety margins, cost effectiveness, availability and diverse activities. This study reviewed various mechanisms of anti-cancer activities of some medicinal plants from a biochemical perspective. The mechanisms of anti-cancer activities of plant compounds addressed in this article include induction of apoptosis, anti-angiogenic effects, anti-metastasis, inhibition of cell cycle, inhibition of DNA destruction and effects on key enzymes, cytotoxic and anti-oxidant effects. The anti-cancer activities of some of the plants involve more than one mechanism.
    Keywords:  anti-cancer activity; biochemical perspectives; mechanism of actions; medicinal plants
    DOI:  https://doi.org/10.1515/jbcpp-2021-0257
  22. J Food Biochem. 2021 Dec 19. e14024
    Ongoing and potential novel trends of pomegranate fruit peel; a comprehensive review of its health benefits and future perspectives as nutraceutical.
    Heba A Fahmy, Mohamed A Farag.
      Pomegranate is an ancient shrub, globally distributed nowadays. It has been used in the middle east as a medicinal food and traditional medicine for thousands of years. Pomegranate peel (PP) constitutes about 50% of the total fruit, however, it has been previously regarded as a waste. Recent research points to PP as a rich source of phenolics (e.g., ellagitannins, flavonoids, and anthocyanins), polysaccharides, in addition to its biotransformed metabolites viz. urolithins making it a valuable waste with promising pharmacological actions. Compared to the pulp and the juice, PP exhibited stronger antioxidant and antimicrobial activities. Besides, it inhibited inflammation in several conditions, including colitis, arthritis, hepatitis, contact dermatitis, and lung inflammation. Moreover, it displayed anti-osteoporosis, anti-hyperglycemic, antidiabetic, antihypertensive, vasculoprotective, hepatoprotective, neuroprotective, and immunomodulatory effects. Additionally, it was effective as a prebiotic and in obesity control, besides it promoted wound healing. Furthermore, PP demonstrated anticancer effects against different cancer types, for example, colon, liver, thyroid, uterine, breast, bladder, prostate, leukemia, and osteosarcoma. Despite PP safety, it may interfere with the metabolism of other drugs because it inhibits cytochromes (CYP) changing their bioavailability, effectiveness, and toxicity. PP biowaste valorization not only avoids against its environmental and economic burden but can also provide a promising platform to produce novel or improved nutraceuticals. This study provides a comprehensive overview of PP biological activities with the reported action mechanisms related to its phytochemicals and further biotransformed metabolites inside the body. Future research prospects to unravel the merits of such waste and optimize its use are discussed. PRACTICAL APPLICATION: Pomegranate is widely distributed throughout the world. Although its peel was previously considered a waste, recent research regards it as a rich source of bioactive compounds with promising biological activities. Its recycling not only overcomes the bio-waste problems, but also provides a source of valuable compounds with several health benefits. In recent years, PP has been demonstrated to exhibit excellent pharmacological bioactivities, for example, antioxidant, anti-inflammatory, antimicrobial, antiosteoporosis, antihyperlipidemic, and anticancer activities. Its health-promoting power is mostly attributed to the phenolic and polysaccharide content, in addition to its amazing biotransformed metabolites. The underlying action mechanisms of such pharmacological activities are discussed and related to its chemical content. This review presents the latest research progress on the role of PP in the prevention and treatment of various chronic diseases, and its protective health effects for future research to be used in nutraceuticals.
    Keywords:   Punica granatum ; anticancer; antimicrobial; antioxidant; biological activities; pomegranate peel
    DOI:  https://doi.org/10.1111/jfbc.14024
  23. Biomolecules. 2021 Dec 04. pii: 1831. [Epub ahead of print]11(12):
    Butyrate and Metformin Affect Energy Metabolism Independently of the Metabolic Phenotype in the Tumor Therapy Model.
    Felix B Meyer, Christian Marx, Sonja B Spangel, René Thierbach.
      The BALB/c cell transformation assay (BALB-CTA) considers inter- and intra-tumor heterogeneities and affords the possibility of a direct comparison between untransformed and malignant cells. In the present study, we established monoclonal cell lines that originate from the BALB-CTA and mimic heterogeneous tumor cell populations, in order to investigate phenotype-specific effects of the anti-diabetic drug metformin and the short-chain fatty acid butyrate. Growth inhibitory effects were measured with a ViCell XR cell counter. The BALB/c tumor therapy model (BALB-TTM) was performed, and the extracellular glucose level was measured in the medium supernatant. Using a Seahorse Analyzer, the metabolic phenotypes of four selected clones were characterized, and effects on energy metabolism were investigated. Anti-carcinogenic effects and reduced glucose uptake after butyrate application were observed in the BALB-TTM. Metabolic characterization of the cell clones revealed three different phenotypes. Surprisingly, treatment with metformin or butyrate induced opposite metabolic shifts with similar patterns in all cell clones tested. In conclusion, the BALB-TTM is a relevant model for mechanistic cancer research, and the generation of monoclonal cell lines offers a novel possibility to investigate specific drug effects in a heterogeneous tumor cell population. The results indicate that induced alterations in energy metabolism seem to be independent of the original metabolic phenotype.
    Keywords:  butyrate; cancer metabolism; metabolic phenotype; metformin; monoclonal cell lines; tumor heterogeneity; tumor therapy
    DOI:  https://doi.org/10.3390/biom11121831
  24. Molecules. 2021 Dec 11. pii: 7521. [Epub ahead of print]26(24):
    Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria.
    Sijongesonke Peter, Siphesihle Jama, Sibusiso Alven, Blessing A Aderibigbe.
      Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria.
    Keywords:  artemisinin; cancer; combination therapy; hybrid compounds; malaria; multidrug resistance
    DOI:  https://doi.org/10.3390/molecules26247521
  25. Int J Mol Sci. 2021 Dec 12. pii: 13346. [Epub ahead of print]22(24):
    Synergistic Effect of Repolarization of M2 to M1 Macrophages Induced by Iron Oxide Nanoparticles Combined with Lactate Oxidase.
    Zi-Xian Liao, Da-Liang Ou, Ming-Jung Hsieh, Chia-Chen Hsieh.
      Metabolic reprogramming of tumors with the accompanying reprogramming of glucose metabolism and production of lactate accumulation is required for the subsequent development of tumors. Recent evidence has indicated that tumor-secreted lactate can promote an oncolytic immune microenvironment within the tumor. Furthermore, tumor-secreted lactate directly induces polarization of tumor-supportive M2 macrophages. However, oxidized tumor-secreted lactate in the tumor microenvironment can be exploited. Iron oxide nanoparticles have shown promising anticancer potential by activating tumor-suppressing macrophages. Furthermore, lactate oxidase (LOX) generally oxidizes tumor-secreted lactate and subsequently converts to pyruvate. Particularly, the ratio of M2 macrophages to M1 macrophages corresponds with tumor growth. In this study, we present iron oxide nanoparticles with carboxylic acid combined with LOX that enhance antitumor efficacy as a synergistic effect on the repolarization of tumor-supportive M2 macrophages to tumor-suppressive M1 macrophages in a tumor microenvironment. After M2 macrophages treated with iron oxide nanoparticles were combined with LOX, the ratio of M1 macrophages was significantly greater than iron oxide nanoparticles alone or with LOX alone. It is concluded that the inhibition of cancer cell proliferation by ratio of M1 macrophages was observed. This study suggests that the iron oxide nanoparticles combined with LOX could be potentially used for potentiating immune checkpoint inhibitor therapies for cancer treatment.
    Keywords:  iron oxide nanoparticles; lactate; lactate oxidase; macrophage; synergistic effect
    DOI:  https://doi.org/10.3390/ijms222413346
  26. Photodiagnosis Photodyn Ther. 2021 Dec 16. pii: S1572-1000(21)00501-9. [Epub ahead of print] 102684
    Multifunctional nanoplatform based on g-C3N4, loaded with MnO2 and CuS nanoparticals for oxygen self-generation photodynamic/photothermal synergistic therapy.
    Miaomiao Li, Mucang Xiao, Qilin Pan, Jianwen Xiong.
      Photodynamic therapy (PDT) and photothermal therapy (PTT) are both novel and promising therapeutic approaches for cancer. Unfortunately, the anticancer efficiency of PDT is restricted by the hypoxic tumor microenvironment and the performance of the photosensitizer (PS) while the efficiency of PTT is limited by the penetration depth of NIR light, making it difficult to further improve the treatment efficiency. In this paper, we strategically proposed a multifunctional nano-platform based on g-C3N4 and loaded with CuS and MnO2 nanoparticals. Interestingly, the obtained F127@CNs-CuS/MnO2 nano-platform with high singlet oxygen quantum yield and excellent photothermal performance were used in synergistic PTT and PDT therapy to cope with the limitation of single mode cancer treatment under irradiation and has greatly improved the treatment effect. Additionally, MnO2 nanoparticles loaded on the CNs surface could not only generate oxygen to ameliorate hypoxia in the tumor environment by reacting with H2O2 in tumor cells, but also react with the over-expressed reduced glutathione (GSH) in cancer cells to further improve the synergistic therapeutic effect. In the in vitro hepatocarcinoma cell inactivation experiment, the maximum cell inactivation efficiency of the PDT, PTT and PDT/PTT synergistic treatment group reached at 65% (F127@CNs-MnO2), 69.2% (CNs-MnO2) and 88.6% (F127@CNs-MnO2) respectively, which means that the F127@CNs-CuS/MnO2-mediated PTT/PDT synergy anticancer treatment was more effective than single mode therapy. In summary, the innovative multifunctional nanoplatform F127@CNs-CuS/MnO2 used for synergistic PTT and PDT treatment has greatly improved the inactivation efficiency of cancer cells and provided a new scheme for the treatment of hypoxic tumors.
    Keywords:  PTT/PDT synergistic treatment; Photosensitizer; hypoxic microenvironment; multifunctional nano-platform
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102684
  27. Phytother Res. 2021 Dec 23.
    Quercetin attenuates the cardiotoxicity of doxorubicin-cyclophosphamide regimen and potentiates its chemotherapeutic effect against triple-negative breast cancer.
    Puwei Zhang, Jianing Zhang, Lin Zhao, Shizheng Li, Kun Li.
      Doxorubicin combined with cyclophosphamide (AC) is the most commonly used regimen for triple-negative breast cancer (TNBC) chemotherapy; however, its clinical application is severely limited by its serious adverse effect on cardiomyocytes. The cardiotoxicity of AC is mainly the result of oxidative stress caused by the imbalance between reactive oxygen species (ROS) and antioxidants, and it also involves multiple signaling pathways. Quercetin (Que) has been proven to possess strong antioxidant activity, and therefore we investigated whether it had potential protective effect against AC-induced cardiotoxicity. Meanwhile, we also evaluated its effect on the antitumor activity of AC. Our in vitro studies showed that Que could attenuate AC-induced cardiotoxicity by inhibiting ROS accumulation and activating ERK1/2 pathway in cardiomyocytes, but interestingly, Que could enhance the antitumor activity of AC by inhibiting ROS accumulation and ERK1/2 pathway in TNBC cells. In addition, our in vivo studies further confirmed that Que could enhance the chemotherapeutic effect of AC against TNBC while it reduced the injury of cardiotoxicity induced by AC. Therefore, Que could be used as a novel agent for the treatment of cardiotoxicity induced by AC regimen in TNBC chemotherapy.
    Keywords:  ERK1/2 pathway; ROS; cyclophosphamide; doxorubicin; quercetin; triple-negative breast cancer
    DOI:  https://doi.org/10.1002/ptr.7342
  28. Curr Med Chem. 2021 Dec 20.
    Nanoparticles mediated target-specific drug delivery in prostate cancer: In-depth review.
    Tarun Kumar Upadhyay, Mohammed Irfan Ali, Fahad Khan, Harsh Goel, Manas Mathur, Keshav Goyal, Sarmad Moin, Pratibha Pandey, Pranay Tanwar, Amit Baran Sharangi, Saloni Dinesh Chandra Gautam, Jhanvi Kiran Kapdi, Kruti Indravadan Patel, Meghna Vipulbhai Patel, Amisha M Parmar, Mohammad Amjad Kamal.
      Nanotechnology has been extensively exploited for its enormous therapeutics and diagnostics potential in the management of multiple disorders. It employs nanomaterials as drug carriers with enhanced efficacy and limited side effects on normal tissues. A lot of nanomaterials have been studied and produced, imminently reforming the treatment and diagnostics of numerous malignancies including cancer. The purpose of the present study is to explore the role of nanotechnology-based devices/therapies that have a vital function in the therapeutics and diagnostics of cancer with potential impact at three levels: early detection, tumor imaging, and drug delivery methods. Concentrating on cancer, promising nanotechnology-based approaches have been planned to satisfy the need for targeted specificity of traditional agents of chemotherapeutics, in addition to early recognition of malignant and precancerous lesions. Prostate cancer is the fifth utmost well-known cancer worldwide and the second most usually detected cancer in men. Therefore, there is a crucial need to improve therapeutic prospects for the diagnosis and treatment of prostate cancer via exploitation of the potential of nanomaterials for cell-targeted specificity and improved primary diagnosis of precancerous tumours. The present review, therefore, focuses on summarizing all prospective applications of nanotechnology in the prognosis and diagnosis of prostate cancer, which would further help researchers to elucidate a more potent therapeutic approach for the better management of prostate cancer in the days ahead.
    Keywords:  Cancer cell; Cytotoxicity; Nanoparticles; Prostate cancer; Targeted delivery
    DOI:  https://doi.org/10.2174/0929867329666211221112312
  29. Life Sci. 2021 Dec 21. pii: S0024-3205(21)01244-3. [Epub ahead of print] 120257
    The emerging roles of nitric oxide in ferroptosis and pyroptosis of tumor cells.
    Qiangqiang He, Meiyu Qu, Chengyun Xu, Wei Shi, Musaddique Hussain, Guojian Jin, Haibin Zhu, Ling-Hui Zeng, Ximei Wu.
      Tumor cells can develop resistance to cell death which is divided into necrosis and programmed cell death (PCD). PCD, including apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Ferroptosis and pyroptosis, two new forms of cell death, have gradually been of interest to researchers. Boosting ferroptosis and pyroptosis of tumor cells could be a potential cancer therapy. Nitric oxide (NO) is a ubiquitous, lipophilic, highly diffusible, free-radical signaling molecule that plays various roles in tumorigenesis. In addition, NO also has regulatory mechanisms through S-nitrosylation that do not depend on the classic NO/sGC/cGMP signaling. The current tumor treatment strategy for NO is to promote cell death through promoting S-nitrosylation-induced apoptosis while multiple drawbacks dampen this tumor therapy. However, numerous studies have suggested that suppression of NO is perceived to active ferroptosis and pyroptosis, which could be a better anti-tumor treatment. In this review, ferroptosis and pyroptosis are described in detail. We summarize that NO influences ferroptosis and pyroptosis and infer that S-nitrosylation mediates ferroptosis- and pyroptosis-related signaling pathways. It could be a potential cancer therapy different from NO-induced apoptosis of tumor cells. Finally, the information shows the drugs that manipulate endogenous production and exogenous delivery of NO to modulate the levels of S-nitrosylation.
    Keywords:  Cancer therapy; Ferroptosis; Nitric oxide; Pyroptosis; S-nitrosylation
    DOI:  https://doi.org/10.1016/j.lfs.2021.120257
  30. Cancers (Basel). 2021 Dec 08. pii: 6184. [Epub ahead of print]13(24):
    Current Landscape of Sonodynamic Therapy for Treating Cancer.
    Toshihiro Yamaguchi, Shuji Kitahara, Kaori Kusuda, Jun Okamoto, Yuki Horise, Ken Masamune, Yoshihiro Muragaki.
      Recent advancements have tangibly changed the cancer treatment landscape. However, curative therapy for this dreadful disease remains an unmet need. Sonodynamic therapy (SDT) is a minimally invasive anti-cancer therapy involving a chemical sonosensitizer and focused ultrasound. A high-intensity focused ultrasound (HIFU) beam is used to destroy or denature targeted cancer tissues. Some SDTs are based on unfocused ultrasound (US). In some SDTs, HIFU is combined with a drug, known as a chemical sonosensitizer, to amplify the drug's ability to damage cancer cells preferentially. The mechanism by which US interferes with cancer cell function is further amplified by applying acoustic sensitizers. Combining multiple chemical sonosensitizers with US creates a substantial synergistic effect that could effectively disrupt tumorigenic growth, induce cell death, and elicit an immune response. Therefore, the minimally invasive SDT treatment is currently attracting attention. It can be combined with targeted therapy (double-targeting cancer therapy) and immunotherapy in the future and is expected to be a boon for treating previously incurable cancers. In this paper, we will consider the current state of this therapy and discuss parts of our research.
    Keywords:  DDS; HIFU; PDAC; SDT; cavitation; glioma; prostate cancer
    DOI:  https://doi.org/10.3390/cancers13246184
  31. Biomolecules. 2021 Dec 15. pii: 1888. [Epub ahead of print]11(12):
    Metformin Treatment or PRODH/POX-Knock out Similarly Induces Apoptosis by Reprograming of Amino Acid Metabolism, TCA, Urea Cycle and Pentose Phosphate Pathway in MCF-7 Breast Cancer Cells.
    Thi Yen Ly Huynh, Ilona Oscilowska, Jorge Sáiz, Magdalena Nizioł, Weronika Baszanowska, Coral Barbas, Jerzy Palka.
      It has been considered that proline dehydrogenase/proline oxidase (PRODH/POX) is involved in antineoplastic activity of metformin (MET). The aim of this study is identification of key metabolites of glycolysis, pentose phosphate pathway (PPP), tricarboxylic acids (TCA), urea cycles (UC) and some amino acids in MET-treated MCF-7 cells and PRODH/POX-knocked out MCF-7 (MCF-7crPOX) cells. MCF-7crPOX cells were generated by using CRISPR-Cas9. Targeted metabolomics was performed by LC-MS/MS/QqQ. Expression of pro-apoptotic proteins was evaluated by Western blot. In the absence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to similar inhibition of glycolysis (drastic increase in intracellular glucose and pyruvate) and increase in the utilization of phospho-enol-pyruvic acid, glucose-6-phosphate and some metabolites of TCA and UC, contributing to apoptosis. However, in the presence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to utilization of some studied metabolites (except glucose), facilitating pro-survival phenotype of MCF-7 cells in these conditions. It suggests that MET treatment or PRODH/POX-knock out induce similar metabolic effects (glucose starvation) and glycolysis is tightly linked to glutamine metabolism in MCF-7 breast cancer cells. The data provide insight into mechanism of anticancer activity of MET as an approach to further studies on experimental breast cancer therapy.
    Keywords:  MCF-7crPOX cells; PRODH/POX; glutamine; lactic acid; metformin; proline
    DOI:  https://doi.org/10.3390/biom11121888
  32. J Nanobiotechnology. 2021 Dec 23. 19(1): 443
    Near-infrared light-triggered nano-prodrug for cancer gas therapy.
    Runcong Liu, Yongjun Peng, Ligong Lu, Shaojun Peng, Tianfeng Chen, Meixiao Zhan.
      Gas therapy (GT) has attracted increasing attention in recent years as a new cancer treatment method with favorable therapeutic efficacy and reduced side effects. Several gas molecules, such as nitric oxide (NO), carbon monoxide (CO), hydrogen (H2), hydrogen sulfide (H2S) and sulfur dioxide (SO2), have been employed to treat cancers by directly killing tumor cells, enhancing drug accumulation in tumors or sensitizing tumor cells to chemotherapy, photodynamic therapy or radiotherapy. Despite the great progress of gas therapy, most gas molecules are prone to nonspecific distribution when administered systemically, resulting in strong toxicity to normal tissues. Therefore, how to deliver and release gas molecules to targeted tissues on demand is the main issue to be considered before clinical applications of gas therapy. As a specific and noninvasive stimulus with deep penetration, near-infrared (NIR) light has been widely used to trigger the cleavage and release of gas from nano-prodrugs via photothermal or photodynamic effects, achieving the on-demand release of gas molecules with high controllability. In this review, we will summarize the recent progress in cancer gas therapy triggered by NIR light. Furthermore, the prospects and challenges in this field are presented, with the hope for ongoing development.
    DOI:  https://doi.org/10.1186/s12951-021-01078-x
  33. Molecules. 2021 Dec 14. pii: 7561. [Epub ahead of print]26(24):
    Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy.
    Ozge Tatli, Gizem Dinler Doganay.
      Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.
    Keywords:  PI3K-mTOR; RAS effectors; RAS-driven cancers; Raf/MEK/Erk
    DOI:  https://doi.org/10.3390/molecules26247561
  34. Angew Chem Int Ed Engl. 2021 Dec 21.
    Coordinating the mechanism of actions of ferroptosis and photothermal effect for cancer theranostics.
    Fantian Zeng, Longguang Tang, Qianyu Zhang, Changrong Shi, Zicheng Huang, Sureya Nijiati, Xiaoyuan Chen, Zijian Zhou.
      Combination therapy based on different mechanisms of cell death has shown promises in tumor therapy. However, design considerations for integrating different modalities are often lack of rationale to synergize the therapeutic effects to the maximal extent. Here, we report a cancer theranostic nanomedicine formula by attentively considering the mechanisms of action of ferroptosis and photothermal effect in combination therapy. We applied the croconaine molecule as both a photothermal converter and an iron-chelating agent which could be readily encapsulated with BSA thus attaining biocompatible and stable Cro-Fe@BSA nanoparticles. The Cro-Fe@BSA nanoprticles in the tumor milieu showed an activated photothermal effect which could enhance the radical formation due to the temperature-dependent Fenton reaction kinetics, while the radical formation during ferroptosis could in turn destruct the heat-induced formation of heat shock proteins, thus preventing the self-protection mechanism of cancer cells in response to heat. This mutually beneficial strategy led to an efficient anticancer effect both in vitro and in a subcutaneous mouse tumor model. Furthermore, the activatable photoacoustic and magnetic resonance imaging performance of the Cro-Fe@BSA nanoparticles provided an intelligent paradigm for safe and reliable cancer theranostics. This study may open up new avenues in designing nanomedicines from a vantage point of synergizing different therapeutic modalities.
    Keywords:  Ferroptosis; Photothermal; cancer theranostics; combination therapy; nanomedicine
    DOI:  https://doi.org/10.1002/anie.202112925
  35. Cancers (Basel). 2021 Dec 11. pii: 6233. [Epub ahead of print]13(24):
    Therapeutic Targets of KRAS in Colorectal Cancer.
    Shafia Rahman, Shimon Garrel, Michael Gerber, Radhashree Maitra, Sanjay Goel.
      Patients with metastatic colorectal cancer have a 5-year overall survival of less than 10%. Approximately 45% of patients with metastatic colorectal cancer harbor KRAS mutations. These mutations not only carry a predictive role for the absence of response to anti-EGFR therapy, but also have a negative prognostic impact on the overall survival. There is a growing unmet need for a personalized therapy approach for patients with KRAS-mutant colorectal cancer. In this article, we focus on the therapeutic strategies targeting KRAS- mutant CRC, while reviewing and elaborating on the discovery and physiology of KRAS.
    Keywords:  KRAS mutation; colorectal cancer; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13246233
  36. Front Pharmacol. 2021 ;12 731741
    Immune Effect of Active Components of Traditional Chinese Medicine on Triple-Negative Breast Cancer.
    Wenjie Zhao, Jinhua Liu, Yaqun Li, Zichao Chen, Dongmei Qi, Zhen Zhang.
      Triple-negative breast cancers are heterogeneous, poorly prognostic, and metastatic malignancies that result in a high risk of death for patients. Targeted therapy for triple-negative breast cancer has been extremely challenging due to the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Clinical treatment regimens for triple-negative breast cancer are often based on paclitaxel and platinum drugs, but drug resistance and side effects from the drugs frequently lead to treatment failure, thus requiring the development of new therapeutic platforms. In recent years, research on traditional Chinese medicine in modulating the immune function of the body has shown that it has the potential to be an effective treatment option against triple-negative breast cancer. Active components of herbal medicines such as alkaloids, flavonoids, polyphenols, saponins, and polysaccharides have been shown to inhibit cancer cell proliferation and metastasis by activating inflammatory immune responses and can modulate tumor-related signaling pathways to further inhibit the invasion of triple-negative breast cancer. This paper reviews the immunomodulatory mechanisms of different herbal active ingredients against triple-negative breast cancer and provides an outlook on the challenges and directions of development for the treatment of triple-negative breast cancer with herbal active ingredients.
    Keywords:  anti-tumor; herbal remedies active ingredients; traditional Chinese medicine; triple-negative breast cancer; tumor immunity
    DOI:  https://doi.org/10.3389/fphar.2021.731741
  37. Angew Chem Int Ed Engl. 2021 Dec 19.
    Smart Nano-PROTACs Reprogram Tumor Microenvironment for Activatable Photo-metabolic Cancer Immunotherapy.
    Chi Zhang, Shasha He, Ziling Zeng, Penghui Cheng, Kanyi Pu.
      Immunosuppressive tumor microenvironment (TME) has been one of the major hurdles to cancer immunotherapy. Protease inhibitors have emerged to be a potential way to modulate intratumoral metabolic processes to reprogram TME, which however suffer from the limited efficacy and off-targeted side effects. We herein report smart nano-proteolysis targeting chimeras (nano-PROTACs) with phototherapeutic ablation and cancer-specific protein degradation to reprogram TEM for photo-metabolic cancer immunotherapy. This nano-PROTAC (SPNCOX) has a semiconducting polymer backbone linked with cyclooxygenase 1/2 (COX-1/2)-targeting PROTAC peptide (CPP) brushes via a cathepsin B (CatB)-cleavable segment. In the presence of the tumor-overexpressed CatB, CPP can be specifically activated to induce targeted intratumoral degradation of COX-1/2 via the ubiquitin-proteasome system. The persistent and effective degradation of COX-1/2 depletes their metabolite, prostaglandin E2 (PGE2) which is an immunosuppressive regulator responsible for activation of immune suppressor cells. Additionally, SPNCOX-mediated phototherapy improves tumor immunogenicity via inducing immunogenic cell death (ICD). Such a smart PROTAC strategy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity, which consequently inhibits tumor growth, metastasis, and recurrence. Thus, this study contributes to advancing PROTACs in cancer immunotherapy.
    Keywords:  cancer immunotherapy; nanoparticles; photodynamic therapy
    DOI:  https://doi.org/10.1002/anie.202114957
  38. Cell Death Discov. 2021 Dec 20. 7(1): 395
    Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin.
    Sunsook Hwang, Seungyeon Yang, Minjoong Kim, Youlim Hong, Byungjoo Kim, Eun Kyung Lee, Seung Min Jeong.
      The DNA damage response is essential for sustaining genomic stability and preventing tumorigenesis. However, the fundamental question about the cellular metabolic response to DNA damage remains largely unknown, impeding the development of metabolic interventions that might prevent or treat cancer. Recently, it has been reported that there is a link between cell metabolism and DNA damage response, by repression of glutamine (Gln) entry into mitochondria to support cell cycle arrest and DNA repair. Here, we show that mitochondrial Gln metabolism is a crucial regulator of DNA damage-induced cell death. Mechanistically, inhibition of glutaminase (GLS), the first enzyme for Gln anaplerosis, sensitizes cancer cells to DNA damage by inducing amphiregulin (AREG) that promotes apoptotic cell death. GLS inhibition increases reactive oxygen species production, leading to transcriptional activation of AREG through Max-like protein X (MLX) transcription factor. Moreover, suppression of mitochondrial Gln metabolism results in markedly increased cell death after chemotherapy in vitro and in vivo. The essentiality of this molecular pathway in DNA damage-induced cell death may provide novel metabolic interventions for cancer therapy.
    DOI:  https://doi.org/10.1038/s41420-021-00792-7
  39. Breast Cancer (Dove Med Press). 2021 ;13 675-689
    Potentiating the Cytotoxic Activity of a Novel Simvastatin-Loaded Cubosome against Breast Cancer Cells: Insights on Dual Cell Death via Ferroptosis and Apoptosis.
    Yara E Elakkad, Shimaa Nabil Senousy Mohamed, Nermeen Z Abuelezz.
       Purpose: Female breast cancer is the most prevalent cancer worldwide. Emerging evidence shows that simvastatin (SIM) has promising anticancer activities. However, the underlying mechanisms are not fully elucidated. Increasing reports imply statins can modulate ferroptosis through disrupting reactive oxygen species (ROS) and glutathione peroxidase enzyme (GPX4) levels. However, whether ferroptosis contributes to SIM anticancer activity, especially regarding GPX4 is unclear. Moreover, poor aqueous SIM solubility hinders its delivery in adequate levels to tumor sites. Meanwhile, cubosomes are biocompatible nanocarriers that enhance lipophilic drug delivery. Therefore, in this study, we formulated a novel SIM-loaded cubosome (SIM-CB) and analyzed its cytotoxic activity on MCF-7 cancer cells in comparison with free SIM.
    Methods: The present study tested the cytotoxic activity of SIM-CB on MCF-7 cells, in comparison with SIM using sulphorhodamine assay. We analyzed SIM-CB effect on apoptosis and cell cycle using flowcytometry, and investigated its effect on Bcl-2, caspase 3, ROS, reduced glutathione (GSH), lipid peroxides and GPX4 enzyme. Finally, we tested the persistence of SIM-CB apoptosis and ferroptosis activities on MCF-7 cells in presence of vitamin E, a potent antioxidant and ferroptosis inhibitor.
    Results: SIM-CB was successfully formulated at the nano size. SIM-CB significantly increased simvastatin therapeutic activity, with IC50 of SIM-CB 52% lower than SIM. 95% CI [1.8, 2.7], SD = 0.34 for SIM-CB, and [4.1, 5.2], SD = 0.45 for SIM. Compared with free SIM, SIM-CB doubled total deaths and increased apoptosis (p < 0.05). Moreover, SIM-CB remarkably increased caspase-3, ROS, and lipid peroxide levels but decreased antiapoptotic Bcl-2 protein, GSH, and GPX4 compared with free SIM. Notably, SIM-CB elicited a high distinguished resistance against the inhibitory effects of vitamin E.
    Conclusion: To the best of our knowledge, this study is the first to present SIM-CB as a promising means to enhancing the therapeutic potential of simvastatin against breast cancer cells, through potentiating both apoptosis and ferroptosis.
    Keywords:  MCF-7 breast cancer cells; anticancer; cell death; nanoparticle; statins
    DOI:  https://doi.org/10.2147/BCTT.S336712
  40. Biomolecules. 2021 Dec 01. pii: 1803. [Epub ahead of print]11(12):
    Health Benefits and Pharmacological Properties of Carvone.
    Abdelhakim Bouyahya, Hamza Mechchate, Taoufiq Benali, Rokia Ghchime, Saoulajan Charfi, Abdelaali Balahbib, Pavel Burkov, Mohammad Ali Shariati, Jose M Lorenzo, Nasreddine El Omari.
      Carvone is a monoterpene ketone contained in the essential oils of several aromatic and medicinal plants of the Lamiaceae and Asteraceae families. From aromatic plants, this monoterpene is secreted at different concentrations depending on the species, the parts used, and the extraction methods. Currently, pharmacological investigations showed that carvone exhibits multiple pharmacological properties such as antibacterial, antifungal, antiparasitic, antineuraminidase, antioxidant, anti-inflammatory, and anticancer activities. These studies were carried out in vitro and in vivo and involved a great deal of knowledge on the mechanisms of action. Indeed, the antimicrobial effects are related to the action of carvone on the cell membrane and to ultrastructural changes, while the anti-inflammatory, antidiabetic, and anticancer effects involve the action on cellular and molecular targets such as inducing of apoptosis, autophagy, and senescence. With its multiple mechanisms, carvone can be considered as natural compounds to develop therapeutic drugs. However, other investigations regarding its precise mechanisms of action as well as its acute and chronic toxicities are needed to validate its applications. Therefore, this review discusses the principal studies investigating the pharmacological properties of carvone, and the mechanism of action underlying some of these properties. Moreover, further investigations of major pharmacodynamic and pharmacokinetic studies were also suggested.
    Keywords:  carvone; mechanism of action; pharmacological properties
    DOI:  https://doi.org/10.3390/biom11121803
  41. Biology (Basel). 2021 Dec 03. pii: 1267. [Epub ahead of print]10(12):
    Breast Cancer Cell Subtypes Display Different Metabolic Phenotypes That Correlate with Their Clinical Classification.
    Consuelo Ripoll, Mar Roldan, Maria J Ruedas-Rama, Angel Orte, Miguel Martin.
      Metabolic reprogramming of cancer cells represents an orchestrated network of evolving molecular and functional adaptations during oncogenic progression. In particular, how metabolic reprogramming is orchestrated in breast cancer and its decisive role in the oncogenic process and tumor evolving adaptations are well consolidated at the molecular level. Nevertheless, potential correlations between functional metabolic features and breast cancer clinical classification still represent issues that have not been fully studied to date. Accordingly, we aimed to investigate whether breast cancer cell models representative of each clinical subtype might display different metabolic phenotypes that correlate with current clinical classifications. In the present work, functional metabolic profiling was performed for breast cancer cell models representative of each clinical subtype based on the combination of enzyme inhibitors for key metabolic pathways, and isotope-labeled tracing dynamic analysis. The results indicated the main metabolic phenotypes, so-called 'metabophenotypes', in terms of their dependency on glycolytic metabolism or their reliance on mitochondrial oxidative metabolism. The results showed that breast cancer cell subtypes display different metabophenotypes. Importantly, these metabophenotypes are clearly correlated with the current clinical classifications.
    Keywords:  breast cancer; metabolic profiling; metabolic reprogramming; tumor metabolism
    DOI:  https://doi.org/10.3390/biology10121267
  42. Small Methods. 2021 Jul;5(7): e2100347
    Emerging Biomaterials-Based Strategies for Inhibiting Vasculature Function in Cancer Therapy.
    Minting Liu, Caisheng Wu, Lingjie Ke, Zhiguo Li, Yun-Long Wu.
      The constant feeding of oxygen and nutrients through the blood vasculature has a vital role in maintaining tumor growth. Interestingly, recent endeavors have shown that nanotherapeutics with the strategy to block tumor blood vessels feeding nutrients and oxygen for starvation therapy can be helpful in cancer treatment. However, this field has not been detailed. Hence, this review will present an exhaustive summary of the existing biomaterial based strategies to disrupt tumor vascular function for effective cancer treatment, including hydrogel or nanogel-mediated local arterial embolism, thrombosis activator loaded nano-material-mediated vascular occlusion and anti-vascular drugs that block tumor vascular function, which may be beneficial to the design of anti-cancer nanomedicine by targeting the tumor vascular system.
    Keywords:  biomaterials; cancer therapy; hydrogels; nanotherapeutics; vasculature functional inhibition
    DOI:  https://doi.org/10.1002/smtd.202100347
  43. Foods. 2021 Dec 01. pii: 2952. [Epub ahead of print]10(12):
    The Regulatory Effects and the Signaling Pathways of Natural Bioactive Compounds on Ferroptosis.
    Shenshen Zhang, Ruizhe Hu, Yaping Geng, Ke Chen, Ling Wang, Mustapha Umar Imam.
      Natural bioactive compounds abundantly presented in foods and medicinal plants have recently received a remarkable attention because of their various biological activities and minimal toxicity. In recent years, many natural compounds appear to offer significant effects in the regulation of ferroptosis. Ferroptosis is the forefront of international scientific research which has been exponential growth since the term was coined. This type of regulated cell death is driven by iron-dependent phospholipid peroxidation. Recent studies have shown that numerous organ injuries and pathophysiological processes of many diseases are driven by ferroptosis, such as cancer, arteriosclerosis, neurodegenerative disease, diabetes, ischemia-reperfusion injury and acute renal failure. It is reported that the initiation and inhibition of ferroptosis plays a pivotal role in lipid peroxidation, organ damage, neurodegeneration and cancer growth and progression. Recently, many natural phytochemicals extracted from edible plants have been demonstrated to be novel ferroptosis regulators and have the potential to treat ferroptosis-related diseases. This review provides an updated overview on the role of natural bioactive compounds and the potential signaling pathways in the regulation of ferroptosis.
    Keywords:  ferrroptosis; glutathione peroxidase 4; health-promoting; lipid peroxidation
    DOI:  https://doi.org/10.3390/foods10122952
  44. EXCLI J. 2021 ;20 1488-1498
    Synergistic effects of metformin and curcumin on cytotoxicity of chemotherapy drugs using a gastric cancer cell line model.
    Ehsan Zarei, Youssof Sefidi-Heris, Iraj Saadat.
      Gastric cancer has a weak prognosis and its usual treatments depend on surgery and chemotherapy. These treatments suffer from some drawbacks such as high rates of local recurrence and metastasis, low survival rates, and significantly decreased life quality. Therefore, new therapeutic methods for improved gastric cancer care with minimal side effects seem necessary. Currently, combinatorial treatments for cancer are preferred and recently, metformin (Met) and curcumin (Cur) have been interesting options for this type of therapy. The aim of the present study was to investigate anticancer effects of metformin and curcumin in both single and combinatorial treatment forms on AGS gastric cancer cell line. In comparison to single treatments with each substance, the results of co-treatments with metformin and curcumin indicated synergistic inhibitory effects on cell viability, wound healing, cell migration and invasion, and primary tumor formation. To determine the selective effect of combination of "Met + Cur" on cancerous cells, very low doses of 8 anticancer drugs (cisplatin, carboplatin, oxaliplatin, epirubicin, doxorubicin, docetaxel, paclitaxel, and methotrexate) used in MTT assay were comparatively tested on AGS cancer cells and normal HDF cells for 48 and 72 hours. The results indicated that the combination of "Met + Cur" significantly increased cytotoxic effects of all anticancer drugs of AGS cells. It is while in normal HDF cells, combination of "Met + Cur" along with anticancer drugs had no effect. This can be inferred as selectively additive effect.
    Keywords:  chemotherapy; curcumin; gastric cancer; metformin; synergistic effect
    DOI:  https://doi.org/10.17179/excli2021-4091
  45. Front Oncol. 2021 ;11 787780
    Photodynamic and Photothermal Therapy of Hepatocellular Carcinoma.
    Zhe Fan, Chengjun Zhuang, Shuang Wang, Yewei Zhang.
      Hepatocellular carcinoma (HCC) is the most common primary liver tumor. It is ranked the sixth most common neoplasm and the third most common cause of cancer mortality. At present, the most common treatment for HCC is surgery, but the 5-year recurrence rates are still high. Patients with early stage HCC with few nodules can be treated with resection or radiofrequency ablation (RFA); while for multinodular HCC, transarterial chemoembolization (TACE) has been the first-line treatment. In recent years, based on medical engineering cooperation, nanotechnology has been increasingly applied to the treatment of cancer. Photodynamic therapy and photothermal therapy are effective for cancer. This paper summarizes the latest progress of photodynamic therapy and photothermal therapy for HCC, with the aim of providing new ideas for the treatment of HCC.
    Keywords:  hepatocellular carcinoma; photodynamic therapy; photothermal therapy; review; treatment
    DOI:  https://doi.org/10.3389/fonc.2021.787780
  46. Int J Nanomedicine. 2021 ;16 8159-8184
    Innovative Approaches of Engineering Tumor-Targeting Bacteria with Different Therapeutic Payloads to Fight Cancer: A Smart Strategy of Disease Management.
    Khaled S Allemailem.
      Conventional therapies for cancer eradication like surgery, radiotherapy, and chemotherapy, even though most widely used, still suffer from some disappointing outcomes. The limitations of these therapies during cancer recurrence and metastasis demonstrate the need for better alternatives. Some bacteria preferentially colonize and proliferate inside tumor mass; thus these bacteria can be used as ideal candidates to deliver antitumor therapeutic agents. The bacteria like Bacillus spp., Clostridium spp., E. coli, Listeria spp., and Salmonella spp. can be reprogrammed to produce, transport, and deliver anticancer agents, eg, cytotoxic agents, prodrug converting enzymes, immunomodulators, tumor stroma targeting agents, siRNA, and drug-loaded nanoformulations based on clinical requirements. In addition, these bacteria can be genetically modified to express various functional proteins and targeting ligands that can enhance the targeting approach and controlled drug-delivery. Low tumor-targeting and weak penetration power deep inside the tumor mass limits the use of anticancer drug-nanoformulations. By using anticancer drug nanoformulations and other therapeutic payloads in combination with antitumor bacteria, it makes a synergistic effect against cancer by overcoming the individual limitations. The tumor-targeting bacteria can be either used as a monotherapy or in addition with other anticancer therapies like photothermal therapy, photodynamic therapy, and magnetic field therapy to accomplish better clinical outcomes. The toxicity issues on normal tissues is the main concern regarding the use of engineered antitumor bacteria, which requires deeper research. In this article, the mechanism by which bacteria sense tumor microenvironment, role of some anticancer agents, and the recent advancement of engineering bacteria with different therapeutic payloads to combat cancers has been reviewed. In addition, future prospective and some clinical trials are also discussed.
    Keywords:  anticancer payload; cancer; genetic modifications; nanoparticle; targeted drug-delivery; tumor-targeting bacteria
    DOI:  https://doi.org/10.2147/IJN.S338272
  47. Anticancer Agents Med Chem. 2021 Dec 21.
    Medicinal Plants for Glioblastoma Treatment.
    Shreeja Datta, Ritika Luthra, Navneeta Bharadvaja.
      Glioblastoma, an aggressive brain cancer, demonstrates the least life expectancy among all brain cancers. Because of the regulation of diverse signaling pathways in cancers, the chemotherapeutic approaches used to suppress their multiplication and spreading are restricted. Sensitivity towards chemotherapeutic agents has developed because of the pathological and drug-evading abilities of these diverse mechanisms. As a result, the identification and exploration of strategies or treatments, which can overcome such refractory obstacles to improve glioblastoma response to treatment as well as recovery, is essential. Medicinal herbs contain a wide variety of bioactive compounds, which could trigger aggressive brain cancers, regulate their anti-cancer mechanisms and immune responses to assist in cancer elimination, and cause cell death. Numerous tumor-causing proteins, which facilitate invasion as well as metastasis of cancer, tolerance of chemotherapies, and angiogenesis, are also inhibited by these phytochemicals. Such herbs remain valuable for glioblastoma prevention and its incidence by effectively being used as anti-glioma therapies. This review thus presents the latest findings on medicinal plants using which the extracts or bioactive components are being used against glioblastoma, their mechanism of functioning, pharmacological description as well as recent clinical studies conducted on them.
    Keywords:  Glioblastoma; anticancer; bioactive; herbs; phytochemicals; phytotherapy
    DOI:  https://doi.org/10.2174/1871520622666211221144739
  48. Front Oncol. 2021 ;11 772263
    Metabolic Pathways and Targets in Chondrosarcoma.
    Ida Micaily, Megan Roche, Mohammad Y Ibrahim, Ubaldo Martinez-Outschoorn, Atrayee Basu Mallick.
      Chondrosarcomas are the second most common primary bone malignancy. Chondrosarcomas are characterized by the production of cartilaginous matrix and are generally resistant to radiation and chemotherapy and the outcomes are overall poor. Hence, there is strong interest in determining mechanisms of cancer aggressiveness and therapeutic resistance in chondrosarcomas. There are metabolic alterations in chondrosarcoma that are linked to the epigenetic state and tumor microenvironment that drive treatment resistance. This review focuses on metabolic changes in chondrosarcoma, and the relationship between signaling via isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), hedgehog, PI3K-mTOR-AKT, and SRC, as well as histone acetylation and angiogenesis. Also, potential treatment strategies targeting metabolism will be discussed including potential synergy with immunotherapies.
    Keywords:  IDH; LdhA; PI3K - AKT pathway; chondrosarcoma; lactate dehydrogenase; mTOR; metabolism
    DOI:  https://doi.org/10.3389/fonc.2021.772263
  49. Front Oncol. 2021 ;11 767116
    PKM2 Is the Target of a Multi-Herb-Combined Decoction During the Inhibition of Gastric Cancer Progression.
    Qingmin Sun, Mengyun Yuan, Hongxing Wang, Xingxing Zhang, Ruijuan Zhang, Haidan Wang, Xu Chen, Min Zhu, Shenlin Liu, Jian Wu.
      Gastric cancer is the third leading cause of cancer death worldwide. Traditional Chinese medicine (TCM) is increasingly extensively applied as a complementary therapy for gastric cancer (GC) in China, which shows unique advantages in preventing gastric cancer metastasis. Previous study indicates modified Jian-pi-yang-zheng (mJPYZ) decoction inhibit the progression of gastric cancer by regulating tumor-associated macrophages (TAM). However, it is unclear whether mJPYZ can affect metabolic reprogramming of gastric cancer cells. Here, we showed that mJPYZ effectively attenuated GC cells proliferation, migration and invasion. Meantime, mJPYZ reduced the aerobic glycolysis level of GC cells in vivo and in vitro by regulating the expression and nuclear translocation of PKM2. Overexpression of PKM2 that could reverse the inhibitory effect of mJPYZ, migration and epithelial to mesenchymal transition (EMT). Our results showed PKM2/HIF-1α signaling was the key metabolic regulator of mJPYZ in GC cells. In summary, our present study suggested that abnormal PKM2 is required for maintaining the malignant phenotype of GC cells. The TCM decoction mJPYZ inhibited GC cells growth and EMT by reducing of glycolysis in PKM2 dependent manner. This evidence expanded our understanding of the anti-tumor mechanism of mJPYZ and further indicated mJPYZ a potential anti-tumor agent for GC patients.
    Chemical Compounds Studied in this Article: Rutin (PubChem CID: 5280805); Lobetyolin (PubChem CID: 53486204); Calycosin-7-glucoside (PubChem CID: 71571502); Formononetin (PubChem CID: 5280378); Calycosin (PubChem CID: 5280448); Ononin (PubChem CID: 442813); P-Coumaric Acid (PubChem CID: 637542).
    Keywords:  PKM2; aerobic glycolysis; cancer metabolism; gastric cancer; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fonc.2021.767116
  50. Int J Pharm. 2021 Dec 20. pii: S0378-5173(21)01202-3. [Epub ahead of print] 121396
    PEGylated Liposomal Encapsulation Improves the Antitumor Efficacy of Combretastatin A4 in Murine 4T1 Triple-Negative Breast Cancer Model.
    Farshad Mirzavi, Mehdi Barati, Roghayyeh Vakili-Ghartavol, Mostafa Karimi Roshan, Mohammad Mashreghi, Mohammad Soukhtanloo, Mahmoud Reza Jaafari.
      Combretastatin A4 (CA4), a vascular disrupting agent has been recently proposed as an anticancer agent. However, its low water solubility and low bioavailability limited its clinical efficacy. Overcomingthis issue requires developing new delivery strategies to enhance its anticancer effects. Here, we prepared various PEGylated liposomal formulations containing CA4 composed of different molar ratios of HSPC/DSPE-mPEG2000/Cholesterol/CA4 (F1: 80:5:10:5; F2: 75:5:15:5; F3: 70:5:20:5; F4: 60:5:30:5 and F5: 50:5:40:5) by the thin-film hydration method plus sonication and extrusion. All formulations had a particle diameter of 100-150 nm, a monomodal distribution with low polydispersity index and a negative zeta potential. Among the formulations only F1, F2, and F3 showed a high CA4 encapsulation efficiency; so their anticancer effects on triple-negative breast cancer (TNBC) were investigated in vitro and in vivo. The release study showed that F3 liposomes had significantly lower CA4 release compared to the F1 and F2 liposomes in different pH of 5.5, 6.5, and 7.4. We found that, CA4-loaded liposomes effectively inhibited both proliferation and migration of 4T1 and MDA-MB-231 TNBC cell lines by inducing cell cycle arrest at the G2/M phase and decreasing MMP-2 and MMP-9 expression and activity. In vivo studies revealed that F3 liposomes were highly accumulated at the tumor site and more effectively delayed tumor growth andprolonged the overall survival than other groups in 4T1 breast tumor-bearing mice. Taken together, encapsulation of CA4 in PEGylated F3 liposomes enhances its anti-tumor activity and may be serve as a promising approach for TNBC treatment and merits further investigation.
    Keywords:  Combretastatin A4; Liposome; Triple-negative breast cancer; Vascular disrupting agent
    DOI:  https://doi.org/10.1016/j.ijpharm.2021.121396
  51. Photodiagnosis Photodyn Ther. 2021 Dec 19. pii: S1572-1000(21)00514-7. [Epub ahead of print] 102697
    Recent Advances and Trends in Nanoparticles based Photothermal and Photodynamic Therapy.
    Jamileh Kadkhoda, Ali Tarighatnia, Jaleh Barar, Ayuob Aghanejad, Soodabeh Davaran.
      Light-mediated therapies, including photodynamic therapy (PDT) and photothermal therapy (PTT) have been exploited as minimally invasive techniques for ablation of various tumors. Compared to the conventional techniques, both modalities provide diagnosis, local destroying, and eradicating tumors with minimal side effects to normal tissues and organs. Moreover, developments of light-mediated approaches using nanoparticles (NPs) and photosensitizer (PS) as diagnostic and therapeutic agents have a crucial role in achieving cancer treatment. In recent years, novel nanoplatforms and strategies have been investigated to boost the therapeutic effect beneficially. In this regard, gold, iron oxide, graphene oxide nanoparticles and hybrid nanocomposites attracted much attention in phototherapy. Moreover, the combination of these materials with PS, in the form of hybrid NPs, reduces in vitro and in vivo cytotoxicity, improves their solubility property in the biological environment and enhances the therapeutic effects. In this review, we look into the basic principles of PTT and PDT with their strengths and limitations to treat cancers. We also will discuss light-based nanoparticles and their PTT and PDT applications in the preclinical and clinical translation. Also, recent advances and trends in this field will be discussed along with the clinical challenges of PTT and PDT.
    Keywords:  Cancer; Gold nanoparticles; Graphene oxide; Iron oxide; Photodynamic therapy; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102697
  52. Biomolecules. 2021 Dec 07. pii: 1841. [Epub ahead of print]11(12):
    Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs.
    Kevin Zhai, Alena Mazurakova, Lenka Koklesova, Peter Kubatka, Dietrich Büsselberg.
      Flavonoids are polyphenolic plant secondary metabolites with pleiotropic biological properties, including anti-cancer activities. These natural compounds have potential utility in glioblastoma (GBM), a malignant central nervous system tumor derived from astrocytes. Conventional GBM treatment modalities such as chemotherapy, radiation therapy, and surgical tumor resection are beneficial but limited by extensive tumor invasion and drug/radiation resistance. Therefore, dietary flavonoids-with demonstrated anti-GBM properties in preclinical research-are potential alternative therapies. This review explores the synergistic enhancement of the anti-GBM effects of conventional chemotherapeutic drugs by flavonoids. Primary studies published between 2011 and 2021 on flavonoid-chemotherapeutic synergy in GBM were obtained from PubMed. These studies demonstrate that flavonoids such as chrysin, epigallocatechin-3-gallate (EGCG), formononetin, hispidulin, icariin, quercetin, rutin, and silibinin synergistically enhance the effects of canonical chemotherapeutics. These beneficial effects are mediated by the modulation of intracellular signaling mechanisms related to apoptosis, proliferation, autophagy, motility, and chemoresistance. In this light, flavonoids hold promise in improving current therapeutic strategies and ultimately overcoming GBM drug resistance. However, despite positive preclinical results, further investigations are necessary before the commencement of clinical trials. Key considerations include the bioavailability, blood-brain barrier (BBB) permeability, and safety of flavonoids; optimal dosages of flavonoids and chemotherapeutics; drug delivery platforms; and the potential for adverse interactions.
    Keywords:  brain cancer; flavonoids; glioblastoma; glioma; synergy
    DOI:  https://doi.org/10.3390/biom11121841
  53. Antioxidants (Basel). 2021 Nov 25. pii: 1881. [Epub ahead of print]10(12):
    The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells.
    Tae Woo Kim, Seong-Gyu Ko.
      Chemotherapy is a powerful anti-tumor therapeutic strategy; however, resistance to treatment remains a serious concern. To overcome chemoresistance, combination therapy with anticancer drugs is a potential strategy. We developed a novel herbal extract, JI017, with lower toxicity and lesser side effects. JI017 induced programmed cell death and excessive unfolded protein response through the release of intracellular reactive oxygen species (ROS) and calcium in breast cancer cells. JI017 treatment increased the expression of endoplasmic reticulum (ER) stress markers, including p-PERK, p-eIF2α, ATF4, and CHOP, via the activation of both exosomal GRP78 and cell lysate GRP78. The ROS inhibitors diphenyleneiodonium and N-acetyl cysteine suppressed apoptosis and excessive ER stress by inhibiting Nox4 in JI017-treated breast cancer cells. Furthermore, in paclitaxel-resistant breast cancer cell lines, MCF-7R and MDA-MB-231R, a combination of JI017 and paclitaxel overcame paclitaxel resistance by blocking epithelial-mesenchymal transition (EMT) processes, such as the downregulation of E-cadherin expression and the upregulation of HIF-1α, vimentin, Snail, and Slug expression. These findings suggested that JI017 exerts a powerful anti-cancer effect in breast cancer and a combination therapy of JI017 and paclitaxel may be a potential cancer therapy for paclitaxel resistant breast cancer.
    Keywords:  ER stress; JI017; Nox4; ROS; exosome
    DOI:  https://doi.org/10.3390/antiox10121881
  54. J Nanobiotechnology. 2021 Dec 20. 19(1): 440
    Mitochondria-targeted nanoplatforms for enhanced photodynamic therapy against hypoxia tumor.
    Jiexin Wen, Yong Luo, Hui Gao, Liang Zhang, Xiang Wang, Ju Huang, Tingting Shang, Di Zhou, Dong Wang, Zhigang Wang, Pan Li, Zhaoxia Wang.
       BACKGROUND: Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers.
    RESULTS: The as-synthesized nanoplatforms penetrated deeply into the interior region of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment.
    CONCLUSIONS: This study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment.
    Keywords:  3-Bromopyruvate; Hypoxic tumor; Nanomedicine; Photodynamic therapy; Respiration inhibition
    DOI:  https://doi.org/10.1186/s12951-021-01196-6
  55. Antioxidants (Basel). 2021 Nov 26. pii: 1893. [Epub ahead of print]10(12):
    Dietary Phytoestrogens and Their Metabolites as Epigenetic Modulators with Impact on Human Health.
    Victor Stefan Ionescu, Alexandra Popa, Andrei Alexandru, Emilia Manole, Mihaela Neagu, Sevinci Pop.
      The impact of dietary phytoestrogens on human health has been a topic of continuous debate since their discovery. Nowadays, based on their presumptive beneficial effects, the amount of phytoestrogens consumed in the daily diet has increased considerably worldwide. Thus, there is a growing need for scientific data regarding their mode of action in the human body. Recently, new insights of phytoestrogens' bioavailability and metabolism have demonstrated an inter-and intra-population heterogeneity of final metabolites' production. In addition, the phytoestrogens may have the ability to modulate epigenetic mechanisms that control gene expression. This review highlights the complexity and particularity of the metabolism of each class of phytoestrogens, pointing out the diversity of their bioactive gut metabolites. Futhermore, it presents emerging scientific data which suggest that, among well-known genistein and resveratrol, other phytoestrogens and their gut metabolites can act as epigenetic modulators with a possible impact on human health. The interconnection of dietary phytoestrogens' consumption with gut microbiota composition, epigenome and related preventive mechanisms is discussed. The current challenges and future perspectives in designing relevant research directions to explore the potential health benefits of dietary phytoestrogens are also explored.
    Keywords:  S-equol; arctigenin; dietary phytochemicals; enterolignans; epigenome; gut metabolites; icariin; microbiota; phytoestrogens; resveratrol
    DOI:  https://doi.org/10.3390/antiox10121893
  56. Front Bioeng Biotechnol. 2021 ;9 762489
    Resveratrol-Loaded TPGS-Resveratrol-Solid Lipid Nanoparticles for Multidrug-Resistant Therapy of Breast Cancer: In Vivo and In Vitro Study.
    Wenrui Wang, Mengyang Zhou, Yang Xu, Wei Peng, Shiwen Zhang, Rongjie Li, Han Zhang, Hui Zhang, Shumin Cheng, Youjing Wang, Xinyu Wei, Chengxu Yue, Qingling Yang, Changjie Chen.
      Multidrug resistance (MDR) is a serious problem during cancer therapy. The purpose of the present study was to formulate D-α-Tocopheryl polyethylene glycol 1000 succinate-resveratrol-solid lipid nanoparticles (TPGS-Res-SLNs) to improve its therapeutic efficacy against breast cancer. In this study, the solvent injection method was used to prepare the TPGS-Res-SLNs. It was found that the TPGS-Res-SLNs exhibited zeta potential and drug-loading of -25.6 ± 1.3 mV and 32.4 ± 2.6%, respectively. Therefore, it was evident that the TPGS-Res-SLNs can increase cellular uptake of chemotherapeutic drugs, induce mitochondrial dysfunction, and augment tumor treatment efficiency by inducing apoptosis. Moreover, it was found that SKBR3/PR cells treated with TPGS-Res-SLNs exhibited significant inhibition of cell migration and invasion, as compared with free resveratrol. In addition, results from in vivo SKBR3/PR xenograft tumor models revealed that TPGS-Res-SLNs has better efficacy in promoting apoptosis of tumor cells owing to high therapeutic outcomes on tumors when compared with the efficacy of free resveratrol. In conclusion, the findings of the present study indicate significant potential for use of TPGS-Res-SLNs as an efficient drug delivery vehicle to overcome drug resistance in breast cancer therapy.
    Keywords:  breast cancer; drug delivery; multidrug resistance; resveratrol; solid lipid nanoparticle
    DOI:  https://doi.org/10.3389/fbioe.2021.762489
  57. ACS Appl Mater Interfaces. 2021 Dec 22.
    Dual-Responsive and ROS-Augmented Nanoplatform for Chemo/Photodynamic/Chemodynamic Combination Therapy of Triple Negative Breast Cancer.
    Mengyao Chen, Jingxian Yang, Lulu Zhou, Xiaochun Hu, Chunhui Wang, Keke Chai, Ruihao Li, Lei Feng, Yanting Sun, Chunyan Dong, Shuo Shi.
      Integrating chemodynamic therapy (CDT) and photodynamic therapy (PDT) into one nanoplatform can produce much more reactive oxygen species (ROS) for tumor therapy. Nevertheless, it is still a great challenge to selectively generate sufficient ROS in tumor regions. Meanwhile, CDT and PDT are restricted by insufficient H2O2 content in the tumor as well as by the limited tumor tissue penetration of the light source. In this study, a smart pH/ROS-responsive nanoplatform, Fe2+@UCM-BBD, is rationally designed for tumor combination therapy. The acidic microenvironment can induce the pH-responsive release of doxorubicin (DOX), which can induce tumor apoptosis through DNA damage. Beyond that, DOX can promote the production of H2O2, providing sufficient materials for CDT. Of note, upconversion nanoparticles at the core can convert the 980 nm light to red and green light, which are used to activate Ce6 to produce singlet oxygen (1O2) and achieve upconversion luminescence imaging, respectively. Then, the ROS-responsive linker bis-(alkylthio)alkene is cleaved by 1O2, resulting in the release of Fenton reagent (Fe2+) to realize CDT. Taken together, Fe2+@UCM-BBD exhibits on-demand therapeutic reagent release capability, excellent biocompatibility, and remarkable tumor inhibition ability via synergistic chemo/photodynamic/chemodynamic combination therapy.
    Keywords:  intracellular ROS cycle; pH/ROS dual responsiveness; synergistic therapy; upconversion
    DOI:  https://doi.org/10.1021/acsami.1c14135
  58. J Cell Biochem. 2021 Dec 21.
    The emerging role of selenium metabolic pathways in cancer: New therapeutic targets for cancer.
    Kalishwaralal Kalimuthu, Chenicheri K Keerthana, Manikandan Mohan, Jaison Arivalagan, Johnson Retnaraj Samuel Selvan Christyraj, Michael A Firer, Mohammad Haroon Asif Choudry, Ruby John Anto, Yong J Lee.
      Selenium (Se) is incorporated into the body via the selenocysteine (Sec) biosynthesis pathway, which is critical in the synthesis of selenoproteins, such as glutathione peroxidases and thioredoxin reductases. Selenoproteins, which play a key role in several biological processes, including ferroptosis, drug resistance, endoplasmic reticulum stress, and epigenetic processes, are guided by Se uptake. In this review, we critically analyze the molecular mechanisms of Se metabolism and its potential as a therapeutic target for cancer. Sec insertion sequence binding protein 2 (SECISBP2), which is a positive regulator for the expression of selenoproteins, would be a novel prognostic predictor and an alternate target for cancer. We highlight strategies that attempt to develop a novel Se metabolism-based approach to uncover a new metabolic drug target for cancer therapy. Moreover, we expect extensive clinical use of SECISBP2 as a specific biomarker in cancer therapy in the near future. Of note, scientists face additional challenges in conducting successful research, including investigations on anticancer peptides to target SECISBP2 intracellular protein.
    Keywords:  cancer therapy; glutathione peroxidase-4; selenocysteine; selenocysteine insertion sequence binding protein 2; thioredoxin reductase 1
    DOI:  https://doi.org/10.1002/jcb.30196
  59. Biochim Biophys Acta Mol Basis Dis. 2021 Dec 20. pii: S0925-4439(21)00259-3. [Epub ahead of print] 166326
    Targeted regulation of autophagy using nanoparticles: New insight into cancer therapy.
    Mahshid Deldar Abad Paskeh, Maliheh Entezari, Courtney Clark, Amirhossein Zabolian, Ehsan Ranjbar, Mahdi Vasheghani Farahani, Hossein Saleki, Seyed Omid Sharifzadeh, Fatemeh Bakhtiari Far, Milad Ashrafizadeh, Saeed Samarghandian, Haroon Khan, Saeid Ghavami, Ali Zarrabi, Marek J Łos.
      Normal cells depend on autophagy to maintain cellular homeostasis by recycling damaged organelles and misfolded proteins and degrading toxic agents. Similar to apoptosis, targeting autophagy has been under attention in cancer therapy. However, autophagy has both pro-survival and pro-death functions in tumors, and its targeting requires further elucidation. The current review focuses on using nanoparticles for targeting autophagy in cancer treatment. Nanocarriers can deliver autophagy regulators along with chemotherapeutic agents leading to intracellular accumulation in cancer cells and synergistic cancer therapy. Furthermore, genetic tools such as siRNA and shRNA can be used for targeting molecular components that regulate autophagy, such as the ATG12-ATG5-ATG16L1 complex. A number of nanostructures, such as gold and zinc oxide nanoparticles, can be used to enhance oxidative stress-mediated apoptosis and autophagy, reducing cancer progression. Further, using nanoparticles to modulate autophagy potentiates the anti-tumor effects of cisplatin and gefitinib during chemotherapy. Polymeric nanoparticles, lipid-based nanostructures and carbon-based nanomaterials are among other nanoparticles capable of regulating autophagy in cancer cells. Of note, various regulatory components of autophagy such as ATGs, Beclin-1 and LC3-II can be affected by nanomaterials. Based on the role of nanomaterial-induced autophagy as pro-survival or pro-death, further targeting can potentiate the fight against cancer cells.
    Keywords:  Autophagy; Cell death; Chemotherapy; Drug delivery; Gene therapy; Nanoparticles
    DOI:  https://doi.org/10.1016/j.bbadis.2021.166326
  60. ACS Appl Mater Interfaces. 2021 Dec 19.
    Chiral Cu2-xSe Nanoparticles for Enhanced Synergistic Cancer Chemodynamic/Photothermal Therapy in the Second Near-Infrared Biowindow.
    Yaofa Liu, Haimei Li, Shulan Li, Xiaoyang Zhang, Jiaqiang Xiong, Fenglei Jiang, Yi Liu, Peng Jiang.
      Chiral nanomaterials have great potential in improving the clinical therapeutic effect due to the unique chiral selectivity of biosystems. However, such a promising therapeutic strategy has so far received little attention in cancer treatment. Here, we report a first chiral Fenton catalyst, d-/l-penicillamine-modified Cu2-xSe nanoparticles (d-/l-NPs), for enhanced synergistic cancer chemodynamic therapy (CDT) and photothermal therapy (PTT) under the second near-infrared (NIR-II) light irradiation. The chiral effect study of chiral Cu2-xSe NPs on cancer cells shows that d-NPs exhibit stronger CDT-induced cytotoxicity than l -NPs due to the stronger internalization ability. Moreover, the hydroxyl radicals (•OH) produced in d-NP-treated cancer cells via the CDT effect can be further improved by NIR-II light irradiation, thereby increasing the apoptosis of cancer cells. In vivo experiments show that, compared with l-NPs, d-NPs exhibit a stronger photothermal effect on the tumor site under NIR-II light irradiation and could completely eliminate the tumor under the synergistic effect of CDT and PTT. This work shows that the chirality of the surface ligand of the nanomaterials could significantly affect their cancer curative effect, which opens up a new way for the development of anticancer nanomedicine.
    Keywords:  chemodynamic therapy; chirality; near-infrared light; photothermal therapy; synergistic therapy
    DOI:  https://doi.org/10.1021/acsami.1c20486
  61. Cancers (Basel). 2021 Dec 07. pii: 6175. [Epub ahead of print]13(24):
    Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance.
    Michelle K Greene, Michael C Johnston, Christopher J Scott.
      The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its potential to overcome such issues. Studies have showcased the ability of nanomedicines to bypass drug efflux pumps, counteract immune suppression, serve as radioenhancers, correct metabolic disturbances and elicit numerous other effects that collectively alleviate various mechanisms of tumour resistance. Much of this progress can be attributed to the remarkable benefits that nanoparticles offer as drug delivery vehicles, such as improvements in pharmacokinetics, protection against degradation and spatiotemporally controlled release kinetics. These attributes provide scope for precision targeting of drugs to tumours that can enhance sensitivity to treatment and have formed the basis for the successful clinical translation of multiple nanoformulations to date. In this review, we focus on the longstanding reputation of pancreatic cancer as one of the most difficult-to-treat malignancies where resistance plays a dominant role in therapy failure. We outline the mechanisms that contribute to the treatment-refractory nature of these tumours, and how they may be effectively addressed by harnessing the unique capabilities of nanomedicines. Moreover, we include a brief perspective on the likely future direction of nanotechnology in pancreatic cancer, discussing how efforts to develop multidrug formulations will guide the field further towards a therapeutic solution for these highly intractable tumours.
    Keywords:  nanomedicine; pancreatic cancer; resistance
    DOI:  https://doi.org/10.3390/cancers13246175
  62. Cancers (Basel). 2021 Dec 16. pii: 6332. [Epub ahead of print]13(24):
    Targeting KRAS in NSCLC: Old Failures and New Options for "Non-G12c" Patients.
    Francesca Jacobs, Massimiliano Cani, Umberto Malapelle, Silvia Novello, Valerio Maria Napoli, Paolo Bironzo.
      Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene mutations are among the most common driver alterations in non-small cell lung cancer (NSCLC). Despite their high frequency, valid treatment options are still lacking, mainly due to an intrinsic complexity of both the protein structure and the downstream pathway. The increasing knowledge about different mutation subtypes and co-mutations has paved the way to several promising therapeutic strategies. Despite the best results so far having been obtained in patients harbouring KRAS exon 2 p.G12C mutation, even the treatment landscape of non-p.G12C KRAS mutation positive patients is predicted to change soon. This review provides a comprehensive and critical overview of ongoing studies into NSCLC patients with KRAS mutations other than p.G12C and discusses future scenarios that will hopefully change the story of this disease.
    Keywords:  G12C; KRAS; NSCLC; drug resistance; non-G12C; oncogene; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13246332
  63. Int J Mol Sci. 2021 Dec 15. pii: 13455. [Epub ahead of print]22(24):
    Apigenin Induces Autophagy and Cell Death by Targeting EZH2 under Hypoxia Conditions in Gastric Cancer Cells.
    Tae Woo Kim, Hee Gu Lee.
      Hypoxia is a major obstacle to gastric cancer (GC) therapy and leads to chemoresistance as GC cells are frequently exposed to the hypoxia environment. Apigenin, a flavonoid found in traditional medicine, fruits, and vegetables and an HDAC inhibitor, is a powerful anti-cancer agent against various cancer cell lines. However, detailed mechanisms involved in the treatment of GC using APG are not fully understood. In this study, we investigated the biological activity of and molecular mechanisms involved in APG-mediated treatment of GC under hypoxia. APG promoted autophagic cell death by increasing ATG5, LC3-II, and phosphorylation of AMPK and ULK1 and down-regulating p-mTOR and p62 in GC. Furthermore, our results show that APG induces autophagic cell death via the activation of the PERK signaling, indicating an endoplasmic reticulum (ER) stress response. The inhibition of ER stress suppressed APG-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further show that APG induces ER stress- and autophagy-related cell death through the inhibition of HIF-1α and Ezh2 under normoxia and hypoxia. Taken together, our findings indicate that APG activates autophagic cell death by inhibiting HIF-1α and Ezh2 under hypoxia conditions in GC cells.
    Keywords:  ER stress; apigenin; autophagy; hypoxia; resistance
    DOI:  https://doi.org/10.3390/ijms222413455
  64. J Pharmacol Sci. 2022 Jan;pii: S1347-8613(21)00094-3. [Epub ahead of print]148(1): 73-85
    Dihydroartemisinin enhances the inhibitory effect of sorafenib on HepG2 cells by inducing ferroptosis and inhibiting energy metabolism.
    Zhao Cui, Huajing Wang, Shuo Li, Tingting Qin, Hang Shi, Ji Ma, Lanfang Li, Guihua Yu, Tingliang Jiang, Canghai Li.
      Although sorafenib (Sora) shows improved efficacy in clinical liver cancer therapy, its therapeutic efficacy is still greatly limited due to side effects as well as drug resistance. Thus new drug intervention strategies are imperative. Our research showed the combined application of Dihydroartemisinin (DHA) and Sora had a synergistic inhibitory effect on HepG2 and SW480 cells, and DHA enhanced Sora efficacy on xenograft tumor in nude mice. DHA and Sora significantly inhibited the cell energy metabolism by decreasing the ATP synthesis rate of oxidative phosphorylation and glycolysis rate, and induced ferroptosis by increasing the level of lipid reactive oxygen species (L-ROS), labile iron pool (LIP) as well as malondialdehyde (MDA) and decreasing the level of glutathione (GSH) in HepG2 cells. In addition, DHA and Sora significantly decreased the levels of SLC7A11 (xCT), GCLC, GPX4, and HO-1 protein in HepG2 cells. Importantly, the above-mentioned indicators changed more significantly after the combined application of DHA and Sora as compared with Sora. In conclusion, DHA and Sora had the same mechanism, and the combined application of them could have a synergistic anti-tumor effect by inducing ferroptosis and inhibiting energy metabolism in HepG2 cells.
    Keywords:  Dihydroartemisinin; Drug combined application; Energy metabolism; Ferroptosis; Sorafenib
    DOI:  https://doi.org/10.1016/j.jphs.2021.09.008
  65. Colloids Surf B Biointerfaces. 2021 Dec 16. pii: S0927-7765(21)00733-5. [Epub ahead of print]211 112287
    Trimethyl chitosan coated palladium nanoparticles as a photothermal agent and its in vitro evaluation in 2D and 3D model of breast cancer cells.
    Prachi Bangde, Tejal Pant, Ganesh Gaikwad, Ratnesh Jain, Prajakta Dandekar.
      The potential of palladium has been scantily explored in biomedical applications. In the present study, palladium nanoparticles (PdNPs) were synthesized and were successfully coated with trimethyl-chitosan (TMC) to improve their biocompatibility. Coating with TMC improved the nanoparticle accumulation in MDAMB231 breast cancer cells, compared to nanoparticles coated with native chitosan. The TMC coated palladium nanoparticles (TMC/PdNPs) exhibited good biocompatibility and physiological stability, as compared to the plain(uncoated) PdNPs. TMC coated PdNPs resulted in photothermal therapeutic effect, when irradiated with a near-infrared (NIR) laser having the wavelength of 808-nm. The TMC/PdNPs resulted in good cytotoxic effect upon laser treatment in both, 2D monolayers and 3D spheroids of MDAMB231 cells, the latter mimicking the tumor microenvironment. These results clearly indicated that TMC/PdNPs acted as ideal photothermal agents for anti-cancer therapy in combination with a non-invasive near-infrared laser.
    Keywords:  3D spheroids; Breast cancer; Palladium; Photothermal treatment (PTT); Trimethyl chitosan
    DOI:  https://doi.org/10.1016/j.colsurfb.2021.112287
  66. Biomedicines. 2021 Dec 14. pii: 1909. [Epub ahead of print]9(12):
    Polyphenols as Antioxidants for Extending Food Shelf-Life and in the Prevention of Health Diseases: Encapsulation and Interfacial Phenomena.
    Marlene Costa, Zerrin Sezgin-Bayindir, Sonia Losada-Barreiro, Fátima Paiva-Martins, Luciano Saso, Carlos Bravo-Díaz.
      Toxicity caused by the exposure to human-made chemicals and environmental conditions has become a major health concern because they may significantly increase the formation of reactive oxygen species (ROS), negatively affecting the endogenous antioxidant defense. Living systems have evolved complex antioxidant mechanisms to protect cells from oxidative conditions. Although oxidative stress contributes to various pathologies, the intake of molecules such as polyphenols, obtained from natural sources, may limit their effects because of their antioxidant and antimicrobial properties against lipid peroxidation and against a broad range of foodborne pathogens. Ingestion of polyphenol-rich foods, such as fruits and vegetables, help to reduce the harmful effects of ROS, but the use of supramolecular and nanomaterials as delivery systems has emerged as an efficient method to improve their pharmacological and therapeutic effects. Suitable exogenous polyphenolic antioxidants should be readily absorbed and delivered to sites where pathological oxidative damage may take place, for instance, intracellular locations. Many potential antioxidants have a poor bioavailability, but they can be encapsulated to improve their ideal solubility and permeability profile. Development of effective antioxidant strategies requires the creation of new nanoscale drug delivery systems to significantly reduce oxidative stress. In this review we provide an overview of the oxidative stress process, highlight some properties of ROS, and discuss the role of natural polyphenols as bioactives in controlling the overproduction of ROS and bacterial and fungal growth, paying special attention to their encapsulation in suitable delivery systems and to their location in colloidal systems where interfaces play a crucial role.
    Keywords:  biointerfaces; drug delivery systems; encapsulation; free radicals; oxidative stress; polyphenols
    DOI:  https://doi.org/10.3390/biomedicines9121909
  67. J Cell Physiol. 2021 Dec 20.
    Murburn precepts for lactic-acidosis, Cori cycle, and Warburg effect: Interactive dynamics of dehydrogenases, protons, and oxygen.
    Kelath Murali Manoj, Vijay Nirusimhan, Abhinav Parashar, Jesucastin Edward, Daniel Andrew Gideon.
      It is unresolved why lactate is transported to the liver for further utilization within the physiological purview of Cori cycle, when muscles have more lactate dehydrogenase (LDH) than liver. We point out that the answer lies in thermodynamics/equilibriums. While the utilization of NADH for the reduction of pyruvate to lactate can be mediated via the classical mechanism, the oxidation of lactate (with/without the uphill reduction of NAD+ ) necessitates alternative physiological approaches. The latter pathway occurs via interactive equilibriums involving the enzyme, protons and oxygen or diffusible reactive oxygen species (DROS). Since liver has high DROS, the murburn activity at LDH would enable the cellular system to tide over the unfavorable energy barriers of the forward reaction (~476 kJ/mol; earlier miscalculated as ~26 kJ/mole). Further, the new mechanism does not necessitate any "smart decision-making" or sophisticated control by/of proteins. The DROS-based murburn theory explains the invariant active-site structure of LDH isozymes and their multimeric nature. The theoretical insights, in silico evidence and analyses of literature herein also enrich our understanding of the underpinnings of "lactic acidosis" (lowering of physiological pH accompanied by lactate production), Warburg effect (increased lactate production at high pO2 by cancer cells) and approach for cancer therapy.
    Keywords:  Cori cycle; Gibbs free energy of reaction in water; Warburg effect; lactate dehydrogenase; lactic acidosis; murburn concept; murzyme
    DOI:  https://doi.org/10.1002/jcp.30661
  68. Int J Mol Sci. 2021 Dec 07. pii: 13182. [Epub ahead of print]22(24):
    Molecular Effectors of Photodynamic Therapy-Mediated Resistance to Cancer Cells.
    Eric Chekwube Aniogo, Blassan P George, Heidi Abrahamse.
      Photodynamic therapy (PDT) is currently enjoying considerable attention as the subject of experimental research to treat resistant cancers. The preferential accumulation of a non-toxic photosensitizer (PS) in different cellular organelles that causes oxidative damage by combining light and molecular oxygen leads to selective cell killing. However, one major setback, common among other treatment approaches, is tumor relapse and the development of resistance causing treatment failure. PDT-mediated resistance could result from increased drug efflux and decreased localization of PS, reduced light exposure, increased DNA damage repair, and altered expression of survival genes. This review highlights the essential insights of PDT reports in which PDT resistance was observed and which identified some of the molecular effectors that facilitate the development of PDT resistance. We also discuss different perceptions of PDT and how its current limitations can be overturned to design improved cancer resistant treatments.
    Keywords:  autophagy; cancer cells; drug resistance; photodynamic therapy
    DOI:  https://doi.org/10.3390/ijms222413182
  69. Front Pharmacol. 2021 ;12 806091
    Sempervirine Inhibits Proliferation and Promotes Apoptosis by Regulating Wnt/β-Catenin Pathway in Human Hepatocellular Carcinoma.
    Rongcai Yue, Haiping Liu, Yaxin Huang, Jing Wang, Dongmei Shi, Yanping Su, Yufei Luo, Ping Cai, Guilin Jin, Changxi Yu.
      Gelsemium elegans (G. elegans) Benth., recognized as a toxic plant, has been used as traditional Chinese medicine for the treatment of neuropathic pain and cancer for many years. In the present study, we aim to obtain the anti-tumor effects of alkaloids of G. elegans and their active components in hepatocellular carcinoma (HCC) and the potential mechanism was also further investigated. We demonstrated that sempervirine induced HCC cells apoptosis and the apoptosis was associated with cell cycle arrest during the G1 phase, up-regulation of p53 and down-regulation of cyclin D1, cyclin B1 and CDK2. Furthermore, sempervirine inhibited HCC tumor growth and enhances the anti-tumor effect of sorafenib in vivo. In addition, inactivation of Wnt/β-catenin pathway was found to be involved in sempervirine-induced HCC proliferation. The present study demonstrated that alkaloids of G. elegans were a valuable source of active compounds with anti-tumor activity. Our findings justified that the active compound sempervirine inhibited proliferation and induced apoptosis in HCC by regulating Wnt/β-catenin pathway.
    Keywords:  Gelsemium elegans benth.; alkaloids; hepatocellular carcinoma; sempervirine; wnt/β-catenin
    DOI:  https://doi.org/10.3389/fphar.2021.806091
  70. Photodiagnosis Photodyn Ther. 2021 Dec 15. pii: S1572-1000(21)00510-X. [Epub ahead of print] 102693
    Polylactide Nanoparticles Encapsulating Indocyanine Green for Photothermal Therapy of Prostate Cancer Cells.
    Melike Güney Akkurt, Murat Gülsoy.
       BACKGROUND: The aim of this study is to investigate the in vitro phototherapeutic potential of indocyanine green (ICG) loaded polylactide (PLA) nanoparticles on prostate cancer cells.Many attempts at designing drug delivery systems against cancer were made that incorporates ICG as a photothermal, photodynamic or imaging agent. However, most of these systems contain at least one more drug, making it hard to assess the effects of ICG alone.
    METHODS: Nanoparticles (ICGNP) were prepared via nanoprecipitation. The effects of phase volume ratio and ICG concentration on size, loading capacity and encapsulation efficiency were explored. Photothermal and photodynamic properties of ICGNP were examined. PC-3 cells were used for cell viability tests. Irradiation was achieved via custom built 809-nm computer controlled diode laser at 1 W/cm2 (up to 600 J/cm2). Data were analyzed by ANOVA followed by Tukey's test (p≤0.05).
    RESULTS: ICGNP exhibited mean size of 300 nm with low polydispersity, and zeta potential of -14 mV. Upon laser irradiation, ICGNP were capable of causing temperature increase and producing singlet oxygen. On PC-3 cells, ICGNP were proved to be as effective as free ICG in inducing cell death. The measured temperature increase in culture medium and experiments with singlet oxygen quenchers suggest that the decrease in cell viability was mainly the result of photothermal action.
    CONCLUSIONS: ICGNP was effective as a photothermal agent on PC-3 cells but further improvements are required to increase ICG loading capacity for it to be useful on a wide range of cell types.
    Keywords:  Indocyanine green; Nanoparticles; Photodynamic therapy; Poly (lactic acid); Prostate cancer
    DOI:  https://doi.org/10.1016/j.pdpdt.2021.102693
  71. Drug Resist Updat. 2021 Dec 08. pii: S1368-7646(21)00048-0. [Epub ahead of print] 100790
    Why may citrate sodium significantly increase the effectiveness of transarterial chemoembolization in hepatocellular carcinoma?
    Philippe Icard, Luca Simula, Zherui Wu, Diana Berzan, Philippe Sogni, Anthony Dohan, Raphael Dautry, Antoine Coquerel, Hubert Lincet, Mauro Loi, David Fuks.
      Hepatocellular carcinoma (HCC) represents the third cause of cancer death in men worldwide, and its increasing incidence can be explained by the increasing occurrence of non-alcoholic steatohepatitis (NASH). HCC prognosis is poor, as its 5-year overall survival is approximately 18 % and most cases are diagnosed at an inoperable advanced stage. Moreover, tumor sensitivity to conventional chemotherapeutics (particularly to cisplatin-based regimen), trans-arterial chemoembolization (cTACE), tyrosine kinase inhibitors, anti-angiogenic molecules and immune checkpoint inhibitors is limited. Oncogenic signaling pathways, such as HIF-1α and RAS/PI3K/AKT, may provoke drug resistance by enhancing the aerobic glycolysis ("Warburg effect") in cancer cells. Indeed, this metabolism, which promotes cancer cell development and aggressiveness, also induces extracellular acidity. In turn, this acidity promotes the protonation of drugs, hence abrogating their internalization, since they are most often weakly basic molecules. Consequently, targeting the Warburg effect in these cancer cells (which in turn would reduce the extracellular acidification) could be an effective strategy to increase the delivery of drugs into the tumor. Phosphofructokinase-1 (PFK1) and its activator PFK2 are the main regulators of glycolysis, and they also couple the enhancement of glycolysis to the activation of key signaling cascades and cell cycle progression. Therefore, targeting this "Gordian Knot" in HCC cells would be of crucial importance. Here, we suggest that this could be achieved by citrate administration at high concentration, because citrate is a physiologic inhibitor of PFK1 and PFK2. As shown in various in vitro studies, including HCC cell lines, administration of high concentrations of citrate inhibits PFK1 and PFK2 (and consequently glycolysis), decreases ATP production, counteracts HIF-1α and PI3K/AKT signaling, induces apoptosis, and sensitizes cells to cisplatin treatment. Administration of high concentrations of citrate in animal models (including Ras-driven tumours) has been shown to effectively inhibit cancer growth, reverse cell dedifferentiation, and neutralize intratumor acidity, without apparent toxicity in animal studies. Citrate may also induce a rapid secretion of pro-inflammatory cytokines by macrophages, and it could favour the destruction of cancer stem cells (CSCs) sustaining tumor recurrence. Consequently, this "citrate strategy" could improve the tumor sensitivity to current treatments of HCC by reducing the extracellular acidity, thus enhancing the delivery of chemotherapeutic drugs into the tumor. Therefore, we propose that this strategy should be explored in clinical trials, in particular to enhance cTACE effectiveness.
    Keywords:  Citrate; Drug resistance; Hepatocellular carcinoma; Ras signaling; Transarterial chemoembolization; Warburg effect
    DOI:  https://doi.org/10.1016/j.drup.2021.100790
  72. Bioact Mater. 2022 May;11 107-117
    Controlled temperature-mediated curcumin release from magneto-thermal nanocarriers to kill bone tumors.
    A Khodaei, F Jahanmard, H R Madaah Hosseini, R Bagheri, A Dabbagh, H Weinans, S Amin Yavari.
      Systemic chemotherapy has lost its position to treat cancer over the past years mainly due to drug resistance, side effects, and limited survival ratio. Among a plethora of local drug delivery systems to solve this issue, the combinatorial strategy of chemo-hyperthermia has recently received attention. Herein we developed a magneto-thermal nanocarrier consisted of superparamagnetic iron oxide nanoparticles (SPIONs) coated by a blend formulation of a three-block copolymer Pluronic F127 and F68 on the oleic acid (OA) in which Curcumin as a natural and chemical anti-cancer agent was loaded. The subsequent nanocarrier SPION@OA-F127/F68-Cur was designed with a controlled gelation temperature of the shell, which could consequently control the release of curcumin. The release was systematically studied as a function of temperature and pH, via response surface methodology (RSM). The bone tumor killing efficacy of the released curcumin from the carrier in combination with the hyperthermia was studied on MG-63 osteosarcoma cells through Alamar blue assay, live-dead staining and apoptosis caspase 3/7 activation kit. It was found that the shrinkage of the F127/F68 layer stimulated by elevated temperature in an alternative magnetic field caused the curcumin release. Although the maximum release concentration and cell death took place at 45 °C, treatment at 41 °C was chosen as the optimum condition due to considerable cell apoptosis and lower side effects of mild hyperthermia. The cell metabolic activity results confirmed the synergistic effects of curcumin and hyperthermia in killing MG-63 osteosarcoma cells.
    Keywords:  Curcumin; MRI contrast agent; Magnetic hyperthermia; Osteosarcoma
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.09.028
  73. Int J Mol Sci. 2021 Dec 11. pii: 13335. [Epub ahead of print]22(24):
    Ferroptosis in Non-Small Cell Lung Cancer: Progression and Therapeutic Potential on It.
    Jiayu Zou, Li Wang, Hailin Tang, Xiuxiu Liu, Fu Peng, Cheng Peng.
      As a main subtype of lung cancer, the current situation of non-small cell lung cancer (NSCLC) remains severe worldwide with a 19% survival rate at 5 years. As the conventional therapy approaches, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, gradually develop into therapy resistance, searching for a novel therapeutic strategy for NSCLC is urgent. Ferroptosis, an iron-dependent programmed necrosis, has now been widely considered as a key factor affecting the tumorigenesis and progression in various cancers. Focusing on its effect in NSCLC, in different situations, ferroptosis can be triggered or restrained. When ferroptosis was induced in NSCLC, it was available to inhibit the tumor progression both in vitro and in vivo. The dominating mechanism was due to a regulation of the classic ferroptosis-repressed GSH-dependent GPX4 signaling pathway instead of other fractional regulating signal axes that regulated ferroptosis via impacting on the ROS, cellular iron levels, etc. In terms of the prevention of ferroptosis in NSCLC, an GSH-independent mechanism was also discovered, interestingly exhibiting the same upstream as the GPX4 signaling. In addition, this review summarizes the progression of ferroptosis in NSCLC and elaborates their association and specific mechanisms through bioinformatics analysis with multiple experimental evidence from different cascades. Finally, this review also points out the possibility of ferroptosis working as a novel strategy for therapy resistance in NSCLC, emphasizing its therapeutic potential.
    Keywords:  NSCLC; ferroptosis; natural drug; progression; therapy resistance
    DOI:  https://doi.org/10.3390/ijms222413335
  74. Biochem Biophys Res Commun. 2021 Dec 15. pii: S0006-291X(21)01668-5. [Epub ahead of print]589 254-259
    Role of photobleaching process of indocyanine green for killing neuroblastoma cells.
    Elwin D Clutter, Liaohai L Chen, Rong R Wang.
      Indocyanine green (ICG) is an FDA-approved near infrared (NIR) imaging agent for diagnosis and imaging guided surgery. It also exhibits phototoxicity under high-dose NIR irradiation, expanding its application as a photo-therapeutic agent. Since ICG's efficiency as a type II photosensitizer has been controversial due to its low triplet state yield, other mechanisms have been explored. While claims of toxic decomposition products, accompanied by irreversible ICG photobleaching, were proposed as the main mechanism, evidences from systemic studies are lacking. In this work, we aimed to unravel the factors affecting ICG photobleaching and the associated photo-killing effect on neuroblastoma, one of the most common pediatric tumors but often escapes therapy. Specifically, we examined how albumin-induced ICG stabilization affects the ICG photobleaching process, and the effect of photobleached ICG on cell proliferation and viability of neuroblastoma cells. It was found that ICG photobleaching was significant only under aerobic conditions and was more efficient in solutions with higher concentration ICG monomers, which were stabilized from aggregates by the presence of BSA while increasing photobleaching and associated oxygen consumption. Photobleached ICG inhibited cell proliferation, indicating another effect of tumor treatment by ICG. Taken together, while enhanced photobleaching by BSA-bound ICG monomers may reduce the photodynamic effect targeting cellular components, the photoproducts directly contribute to tumor growth inhibition and assist in a secondary mechanism to stop tumor growth.
    Keywords:  Albumin; Dissolved oxygen; Indocyanine green; Photobleaching; Tumor growth inhibition
    DOI:  https://doi.org/10.1016/j.bbrc.2021.12.033
  75. Colloids Surf B Biointerfaces. 2021 Dec 16. pii: S0927-7765(21)00741-4. [Epub ahead of print]211 112295
    Biocompatible BSA-Ag2S nanoparticles for photothermal therapy of cancer.
    Junwei Zhao, Qian Zhang, Wenquan Liu, Guiye Shan, Xin Wang.
      Photothermal therapy (PTT) induced by near-infrared (NIR) laser has attracted much attention for the innovation of tumor therapy, in which the photothermal agent with good biocompatibility and high efficiency is the prerequisite. Herein, the biocompatible bovine serum albumin (BSA) coated Ag2S nanoparticles (NPs) as photothermal agent were synthesized directly at mild temperature for PTT of cancer. The high photothermal conversion efficiency of the obtained Ag2S NPs with strong NIR absorption is about 18.89%, which make them ideal materials for photothermal agents. Furthermore, the Ag2S NPs can induce effective apoptosis of tumor cells exposed to an NIR laser (808 nm), realizing an effective PTT with excellent killing effect of tumor cells. This work provides a simple reproducible method to fabricate the water-soluble and biocompatible Ag2S NPs, which would provide new insights of designing new functional NPs for the PTT therapy of tumor.
    Keywords:  Ag(2)S; Biocompatible; Photothermal effect; Photothermal therapy; Water-soluble
    DOI:  https://doi.org/10.1016/j.colsurfb.2021.112295
  76. J Mater Chem B. 2021 Dec 23.
    Multi-ligand modified PC@DOX-PA/EGCG micelles effectively inhibit the growth of ER+, PR+ or HER2+ breast cancer.
    Xiaozhen Wang, Jiecheng He, Siyuan Jiang, Yifei Gao, Ling-Kun Zhang, Liang Yin, Rong You, Yan-Qing Guan.
      Breast cancer is one of the most common cancers in the world with tumor heterogeneity. Currently, cancer treatment mainly relies on surgical intervention, chemotherapy, and radiotherapy, for which the side effects, drug resistance and cost need to be resolved. In this study, we develop a natural medicine targeted therapy system. Phosphatidylcholine (PC), doxorubicin (DOX), procyanidin (PA), and epigallocatechin gallate (EGCG) are assembled and PC@DOX-PA/EGCG nanoparticles (NPs) are obtained. In addition, the HER2, ER and PR ligands were grafted on the surface of the NPs to acquire the targeted nanoparticles NP-ER, NP-ER-HER2, and NP-ER-HER2-PR. The physicochemical properties of the nanoparticles were detected and it was found that the nanoparticles are spherical and less than 200 nm in diameter. Furthermore, in vitro and in vivo results indicate that the nanoparticles can target BT-474, MCF-7, EMT-6, and MDA-MB-231 breast cancer cells, effectively inhibiting the growth of the breast cancer cells. In short, this research will provide some strategies for the treatment of heterogeneous breast cancer.
    DOI:  https://doi.org/10.1039/d1tb02056k
  77. Small Methods. 2021 Apr;5(4): e2001087
    Engineering Oxygen-Irrelevant Radical Nanogenerator for Hypoxia-Independent Magnetothermodynamic Tumor Nanotherapy.
    Yujia Shen, Caihong Dong, Huijing Xiang, Cuixian Li, Fan Zhuang, Yixin Chen, Qing Lu, Yu Chen, Beijian Huang.
      Tumor hypoxia substantially lowers the treatment efficacy of oxygen-relevant therapeutic modalities because the production of reactive oxygen species in oxygen-relevant anticancer modalities is highly dependent on oxygen level in tumor tissues. Here a distinctive magnetothermodynamic anticancer strategy is developed that takes the advantage of oxygen-irrelevant free radicals produced from magnetothermal decomposable initiators for inducing cancer-cell apoptosis in vitro and tumor suppression in vivo. Free-radical nanogenerator is constructed through in situ engineering of a mesoporous silica coating on the surface of superparamagnetic Mn and Co-doped nanoparticles (MnFe2 O4 @CoFe2 O4 , denoted as Mag) toward multifunctionality, where mesoporous structure provides reservoirs for efficient loading of initiators and the Mag core serves as in situ heat source under alternating magnetic field (AMF) actuation. Upon exposure to an exogenous AMF, the magnetic hyperthermia effect of superparamagnetic core lead to the rapid decomposition of the loaded/delivered initiators (AIPH) to produce oxygen-irrelevant free radicals. Both the magnetothermal effect and generation of toxic free radicals under AMF actuation are synergistically effective in promoting cancer-cell death and tumor suppression in the hypoxic tumor microenvironment. The prominent therapeutic efficacy of this radical nanogenerator represents an intriguing paradigm of oxygen-irrelevant nanoplatform for AMF-initiated synergistic cancer treatment.
    Keywords:  free radicals; magnetic hyperthermia; magnetothermodynamic therapy; nanomedicine; oxygen-irrelevant
    DOI:  https://doi.org/10.1002/smtd.202001087
  78. Biomolecules. 2021 Nov 30. pii: 1790. [Epub ahead of print]11(12):
    Insight into the Double-Edged Role of Ferroptosis in Disease.
    Lei Zhang, Ruohan Jia, Huizhen Li, Huarun Yu, Keke Ren, Shuangshuang Jia, Yanzhang Li, Qun Wang.
      Ferroptosis, a newly described type of iron-dependent programmed cell death that is distinct from apoptosis, necroptosis, and other types of cell death, is involved in lipid peroxidation (LP), reactive oxygen species (ROS) production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for ferroptosis in multiple diseases, including acute kidney injury, cancer, hepatic fibrosis, Parkinson's disease, and Alzheimer's disease. Therefore, ferroptosis has become one of the research hotspots for disease treatment and attracted extensive attention in recent years. This review mainly summarizes the relationship between ferroptosis and various diseases classified by the system, including the urinary system, digestive system, respiratory system, nervous system. In addition, the role and molecular mechanism of multiple inhibitors and inducers for ferroptosis are further elucidated. A deeper understanding of the relationship between ferroptosis and multiple diseases may provide new strategies for researching diseases and drug development based on ferroptosis.
    Keywords:  ROS; ferroptosis; inducers; inhibitors; systemic diseases
    DOI:  https://doi.org/10.3390/biom11121790
  79. Microorganisms. 2021 Nov 25. pii: 2427. [Epub ahead of print]9(12):
    Nutraceuticals and Herbal Food Supplements for Weight Loss: Is There a Prebiotic Role in the Mechanism of Action?
    Alexander Bertuccioli, Marco Cardinali, Marco Biagi, Sara Moricoli, Ilaria Morganti, Giordano Bruno Zonzini, Giovanna Rigillo.
      Numerous nutraceuticals and botanical food supplements are used with the intention of modulating body weight. A recent review examined the main food supplements used in weight loss, dividing them according to the main effects for which they were investigated. The direct or indirect effects exerted on the intestinal microbiota can also contribute to the effectiveness of these substances. The aim of this review is to evaluate whether any prebiotic effects, which could help to explain their efficacy or ineffectiveness, are documented in the recent literature for the main nutraceuticals and herbal food supplements used for weight loss management. Several prebiotic effects have been reported for various nutraceutical substances, which have shown activity on Bifidobacterium spp., Lactobacillus spp., Akkermansia muciniphila, Faecalibacterium prausnitzi, Roseburia spp., and the Firmicutes/Bacteroidetes ratio. Different prebiotics have beneficial effects on weight and the related metabolic profile, in some cases even acting on the microbiota with mechanisms that are completely independent from those nutraceuticals for which certain products are normally used. Further studies are necessary to clarify the different levels at which a nutraceutical substance can exert its action.
    Keywords:  botanicals; food supplements; microbiota; prebiotic; weight loss
    DOI:  https://doi.org/10.3390/microorganisms9122427
  80. Biomed Pharmacother. 2021 Dec 16. pii: S0753-3322(21)01340-8. [Epub ahead of print]146 112553
    The potential role of vitamin C in empowering cancer immunotherapy.
    Takwa Bedhiafi, Varghese Philipose Inchakalody, Queenie Fernandes, Sarra Mestiri, Nashiru Billa, Shahab Uddin, Maysaloun Merhi, Said Dermime.
      Vitamin C also known as L-ascorbic acid is a nutrient naturally occurring in many fruits and vegetables and widely known for its potent antioxidant activity. Several studies have highlighted the importance of using high dose vitamin C as an adjuvant anti-cancer therapy. Interestingly, it has been shown that vitamin C is able to modulate the anti-cancer immune response and to help to overcome the resistance to immune checkpoints blockade (ICB) drugs such as cytotoxic T-lymphocyte antigen 4 (CLTA-4) and programmed cell death ligand 1 (PD-L1/PD-1) inhibitors. Indeed, it was reported that vitamin C regulates several mechanisms developed by cancer cells to escape T cells immune response and resist ICB. Understanding the role of vitamin C in the anti-tumor immune response will pave the way to the development of novel combination therapies that would enhance the response of cancer patients to ICB immunotherapy. In this review, we discuss the effect of vitamin C on the immune system and its potential role in empowering cancer immunotherapy through its pro-oxidant potential, its ability to modulate epigenetic factors and its capacity to regulate the expression of different cytokines involved in the immune response.
    Keywords:  Cancer therapy; Immune checkpoint blockade; Immunotherapy; Vitamin C
    DOI:  https://doi.org/10.1016/j.biopha.2021.112553
  81. Curr Mol Med. 2021 Dec 21.
    Starring role of Biomarkers and Anticancer Agents as a Major Driver in Precision Medicine of Cancer Therapy.
    Suman Kumar Ray, Sukhes Mukherjee.
      Precision medicine represents the most modern contemporary medicine trend, based on enormous amounts of data relating to people's health, individual characteristics, and life context using the most appropriate strategies to prevent and cure them. Precision medicine in cancer coordinates most precisely and viable treatment to every individual cancer patient based on the disease's genetic profile. Precision medicine changes the standard one size fits all medication model, which has focused on average responses to care. Significantly, consolidating different modern methodologies for streamlining and checking anticancer drugs can have continuous effects on understanding results. Precision medicine can help explicit anticancer treatments using various drugs and even in discovery, thus becoming the paradigm of future cancer medicine. Cancer biomarkers are a significant focus point in precision medicine, and findings of different biomarkers make this field more promising and challenging. Naturally, genetic instability and the collection of extra changes in malignant growth cells are ways that cancer cells use to adapt and survive in a hostile environment, for example, one made by these treatment modalities. Precision medicine is centered around recognizing which treatments are best for individual patients, dependent on their malignant growth and genetic characterization. This new era of genomics, which is progressively referred to as precision medicine, has ignited a new episode in the relationship between genomics and anticancer drug development.
    Keywords:  Precision medicine; anticancer drug; cancer biomarkers; genomics; malignant growth; treatment modality
    DOI:  https://doi.org/10.2174/1566524022666211221152947
  82. J Nanobiotechnology. 2021 Dec 18. 19(1): 426
    Nanofactory for metabolic and chemodynamic therapy: pro-tumor lactate trapping and anti-tumor ROS transition.
    Ruiqing He, Jie Zang, Yuge Zhao, Ying Liu, Shuangrong Ruan, Xiao Zheng, Gaowei Chong, Dailin Xu, Yan Yang, Yushan Yang, Tingting Zhang, Jingjing Gu, Haiqing Dong, Yongyong Li.
      Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a "lactate treatment plant" (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors.
    Keywords:  Chemodynamic therapy; Immunogenic cell death; Immunosuppressive tumor microenvironment; Lactate
    DOI:  https://doi.org/10.1186/s12951-021-01169-9
  83. Drug Deliv. 2022 Dec;29(1): 1-9
    A pH-responsive complex based on supramolecular organic framework for drug-resistant breast cancer therapy.
    Yun-Chang Zhang, Pei-Yu Zeng, Zhi-Qiang Ma, Zi-Yue Xu, Ze-Kun Wang, Beibei Guo, Feng Yang, Zhan-Ting Li.
      Chemotherapy is one of the main ways to treat breast cancer clinically. However, the multidrug resistance to anti-tumor drugs limits their clinical use. To overcome these drawbacks, the development of drug delivery systems (DDSs) has attracted more and more attention in cancer therapy. At present, the preparation and purification process are complicated for many reported DDSs, while the clinic calls for new DDSs that are more convenient for preparation. Here a new pH-responsive supramolecular organic framework drug delivery complex loading doxorubicin (DOX) is fabricated. Anti-tumor activity of the system in vitro was investigated by cell cytotoxicity, uptake assay, and cell apoptosis analysis. The anti-tumor activity in vivo was investigated by inspecting nude mice body weight, tumor volume and weight, also a preliminary mechanism probe was conducted by HE and TUNEL staining. The DOX@SOF displayed high stability, good biocompatibility and pH-regulated drug release. At acid condition, the hydrazone bonds would be broken, which result in the dissociation of SOF, and then the drugs would be released from the system. Furthermore, DOX@SOF enhanced cellular internalization. Both in vitro and in vivo experiments reflected that DOX@SOF could enhance the anti-tumor activity of DOX. for the MCF-7/ADR tumor cells and tumors. This study provides a highly efficient strategy to prepare a stimulus-responsive supramolecular drug delivery complex for the treatment of drug-resistant cancer, the results presented inspiring scientific interests in exploring new drug delivery strategies and reversing multi-drug resistance for clinical chemotherapy.
    Keywords:  Supramolecular organic framework; breast cancer; doxorubicin; drug delivery system; drug resistance
    DOI:  https://doi.org/10.1080/10717544.2021.2010839
  84. Front Pharmacol. 2021 ;12 770663
    Platinum and Taxane Based Adjuvant and Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: A Narrative Review.
    Hao Tian, Dandan Ma, Xuanni Tan, Wenting Yan, Xiujuan Wu, Cheng He, Ling Zhong, Yan Zhang, Bingjie Yu, Yi Zhang, Xiaowei Qi.
      Platinum (Pt) derivatives such as cisplatin and carboplatin are the class of drugs with proven activity against triple-negative breast cancer (TNBC). This is due to the ability of Pt compounds to interfere with the DNA repair mechanisms of the neoplastic cells. Taxanes have been efficacious against estrogen receptor-negative tumors and act by disruption of microtubule function. Due to their distinct mechanisms of action and routes of metabolism, the combination of the Pt agents and taxanes results in reduced systemic toxicity, which is ideal for treating TNBC. Also, the sensitivity of BRCA1-mutated cells to taxanes remains unsolved as in vitro evidence indicates resistance against taxanes due to BRCA1 mutations. Recent evidence suggests that the combination of carboplatin and paclitaxel resulted in better pathological complete response (pCR) in patients with TNBC, both in neoadjuvant and adjuvant settings. In vitro studies showed sequential dependency and optimal time scheduling of Pt- and taxane-based chemotherapy. Also, combining carboplatin with docetaxel in the NAC regimen yields an excellent pCR in patients with BRCA-associated and wild-type TNBC. TNBC is a therapeutic challenge that can be tackled by identifying new therapeutic sub-targets and specific cross-sections that can be benefitted from the addition of Pt- and taxane-based chemotherapy. This review summarizes the merits as well as the mechanism of Pt- and taxane-based adjuvant and neoadjuvant chemotherapies in early TNBC from the available and ongoing clinical studies.
    Keywords:  adjuvant chemotherapy; neoadjuvant therapy; platinum; taxane; triple negative breast cancer
    DOI:  https://doi.org/10.3389/fphar.2021.770663
  85. Small Methods. 2021 Dec;5(12): e2100539
    An Efficient Carbon-Based Drug Delivery System for Cancer Therapy through the Nucleus Targeting and Mitochondria Mediated Apoptotic Pathway.
    Junfeng Zhang, Chenchen Li, Qianghua Xue, Xuelian Yin, Yajie Li, Wen He, Xuerui Chen, Jian Zhang, Rui L Reis, Yanli Wang.
      The emergence of nanocarriers solves the problems of antitumor drugs such as non-targeting, huge side effects, etc., and has been widely used in tumor therapy. Some kinds of antitumor drugs such as doxorubicin (DOX) mainly act on the nucleic acid causing DNA damage, interfering with transcription, and thereby disrupting or blocking the process of cancer cell replication. Herein, a new nanodrug delivery system, the carbon-based nanomaterials (CBNs)-Pluronic F127-DOX (CPD), is designed by using CBNs as a nanocarrier for DOX. As a result, the tumor growth inhibition rate of CPD group is as high as 79.42 ± 2.83%, and greatly reduces the side effects. The targeting rate of the CPD group of DOX in the tumor nucleus is 36.78%, and the %ID/g in tumor tissue is 30.09%. The CPD regulates the expression levels of Caspase-3, p53, and Bcl-2 genes by increasing intracellular reactive oxygen species (ROS) levels and reducing mitochondrial membrane potential, which indicates that mitochondrial-mediated pathways are involved in apoptosis. The CPD nanodrug delivery system increases the effective accumulation of DOX in tumor cell nuclei and tumor tissues, and generates massive ROS, thereby inhibiting tumor growth in vivo, representing a promising agent for anticancer applications.
    Keywords:  cancer therapy; carbon-based nanomaterials; doxorubicin; drug delivery; mitochondria mediated apoptotic
    DOI:  https://doi.org/10.1002/smtd.202100539
  86. Expert Rev Vaccines. 2021 Dec 21.
    Cancer vaccines as a targeted immunotherapy approach for breast cancer: an update of clinical evidence.
    Maryam Abbaspour, Vajihe Akbari.
       INTRODUCTION: Breast cancer (BC) is the first common neoplastic malignancy and the second leading cause of death in women worldwide. Conventional treatments for BC are often associated with severe side effects and may even lead to late recurrence. For this reason, in recent years, cancer immunotherapy (e.g., cancer vaccines), a novel approach based on the specificity and amplification of acquired immune responses, has been considered as a potential candidate in particular to treat metastatic BC.
    AREAS COVERED: In this review, we summarize and discuss the recent development of therapeutic vaccines for BC, use of specific BC cellular antigens, antigen selection, and probable causes for their insufficient effectiveness.
    EXPERT OPINION: Despite development of several different BC vaccines strategies including protein/peptide, dendritic cell, and genetic vaccines, until now, no BC vaccine has been approved for clinical use. Most of the current BC vaccines themselves fail to bring clinical benefit to BC patients and are applied in combination with radiotherapy, chemotherapy, or targeted therapy. It is hoped that with advances in our knowledge about tumor microenvironment and the development of novel combination strategies, the tumor immunosuppressive mechanisms can be overcome and prolonged immunologic and effective anti-tumor response can be developed in patients.
    Keywords:  Breast cancer; Cancer immunotherapy; DNA-based vaccine; Dendritic cell vaccines; Peptide-based vaccine
    DOI:  https://doi.org/10.1080/14760584.2022.2021884
  87. EXCLI J. 2021 ;20 1544-1570
    An update of advanced nanoplatforms for Glioblastoma Multiforme Management.
    Mariana Amaral, Nuno Cruz, Ana Rosa, Beatriz Nogueira, Diana Costa, Francisco Santos, Mariana Brazão, Pedro Policarpo, Rita Mateus, Yan Kobozev, Catarina Pinto Reis.
      Glioblastoma multiforme (GBM) is a very aggressive and heterogeneous glioma. Currently, GBM is treated with a combination of surgery, radiotherapy, chemotherapy (e.g. temozolamide) and Tumour Treating Fields. Unfortunately, the mean survival is still around 15 months. This poor prognosis is associated with therapy resistance, tumor recurrence, and limited delivery of drugs due to the blood-brain barrier nature. Nanomedicine, the application of nanotechnology to medicine, has revolutionized many health fields, specifically cancer diagnosis and treatment. This review explores the particularities of different nanosystems (i.e., superparamagnetic, polymeric and gold nanoparticles, and liposomes) as well as how they can be applied to the treatment and diagnosis of GBM. As described, the most of the cited examples are on the preclinical phase; however, positive results were obtained and thus, the distance to achieve an effective treatment is shorter every day.
    Keywords:  Glioblastoma multiforme; gold nanoparticles; liposomes; nanosystems; polymeric nanoparticles; superparamagnetic nanoparticles
    DOI:  https://doi.org/10.17179/excli2021-4393
  88. Nanomaterials (Basel). 2021 Dec 08. pii: 3330. [Epub ahead of print]11(12):
    Novel Perspectives towards RNA-Based Nano-Theranostic Approaches for Cancer Management.
    Rabia Arshad, Iqra Fatima, Saman Sargazi, Abbas Rahdar, Milad Karamzadeh-Jahromi, Sadanand Pandey, Ana M Díez-Pascual, Muhammad Bilal.
      In the fight against cancer, early diagnosis is critical for effective treatment. Traditional cancer diagnostic technologies, on the other hand, have limitations that make early detection difficult. Therefore, multi-functionalized nanoparticles (NPs) and nano-biosensors have revolutionized the era of cancer diagnosis and treatment for targeted action via attaching specified and biocompatible ligands to target the tissues, which are highly over-expressed in certain types of cancers. Advancements in multi-functionalized NPs can be achieved via modifying molecular genetics to develop personalized and targeted treatments based on RNA interference. Modification in RNA therapies utilized small RNA subunits in the form of small interfering RNAs (siRNA) for overexpressing the specific genes of, most commonly, breast, colon, gastric, cervical, and hepatocellular cancer. RNA-conjugated nanomaterials appear to be the gold standard for preventing various malignant tumors through focused diagnosis and delivering to a specific tissue, resulting in cancer cells going into programmed death. The latest advances in RNA nanotechnology applications for cancer diagnosis and treatment are summarized in this review.
    Keywords:  RNA nanotechnology; cancer; nano-biosensor; theranostic
    DOI:  https://doi.org/10.3390/nano11123330
  89. Food Sci Nutr. 2021 Dec;9(12): 6892-6902
    Superfruits in China: Bioactive phytochemicals and their potential health benefits - A Review.
    Jinfang Liu, Duoxia Xu, Shuai Chen, Fang Yuan, Like Mao, Yanxiang Gao.
      The term "superfruit" usually refers to certain fruits, which are rich in antioxidant components, therefore, are beneficial to human health. In China, there has been the concept of health preservation and dietary therapy through food intake in a long history. However, some other superfruits growing mainly in China have not attracted extensive attention, such as Cili, Goji berry, and sea buckthorn. Many studies suggested all of these superfruits showed strong antioxidant effects and anti-inflammatory activity in common. However, there are various other advantages and functions in different fruits. This article reviewed the research findings from the existing literature published about major antioxidant bioactive compounds and the potential health benefits of these fruits. The phytochemicals from superfruits are bioaccessible and bioavailable in humans with promising health benefits. More studies are needed to validate the health benefits of these superfruits. It would provide essential information for further research and functional food development.
    Keywords:  antioxidants; health benefits; phytochemicals; superfruits
    DOI:  https://doi.org/10.1002/fsn3.2614
  90. J Med Chem. 2021 Dec 21.
    Identification of Pyruvate Carboxylase as the Cellular Target of Natural Bibenzyls with Potent Anticancer Activity against Hepatocellular Carcinoma via Metabolic Reprogramming.
    Yuwen Sheng, Yuwen Chen, Zhongqiu Zeng, Wenbi Wu, Jing Wang, Yuling Ma, Yuan Lin, Jichao Zhang, Yulan Huang, Wenhua Li, Qiyu Zhu, Xiao Wei, Suiyan Li, Wisanee Wisanwattana, Fu Li, Wanli Liu, Apichart Suksamrarn, Guolin Zhang, Wei Jiao, Fei Wang.
      Cancer cell proliferation in some organs often depends on conversion of pyruvate to oxaloacetate via pyruvate carboxylase (PC) for replenishing the tricarboxylic acid cycle to support biomass production. In this study, PC was identified as the cellular target of erianin using the photoaffinity labeling-click chemistry-based probe strategy. Erianin potently inhibited the enzymatic activity of PC, which mediated the anticancer effect of erianin in human hepatocellular carcinoma (HCC). Erianin modulated cancer-related gene expression and induced changes in metabolic intermediates. Moreover, erianin promotes mitochondrial oxidative stress and inhibits glycolysis, leading to insufficient energy required for cell proliferation. Analysis of 14 natural analogs of erianin showed that some compounds exhibited potent inhibitory effects on PC. These results suggest that PC is a cellular target of erianin and reveal the unrecognized function of PC in HCC tumorigenesis; erianin along with its analogs warrants further development as a novel therapeutic strategy for the treatment of HCC.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c01605
  91. Front Bioeng Biotechnol. 2021 ;9 785937
    Kinetics of Nanomedicine in Tumor Spheroid as an In Vitro Model System for Efficient Tumor-Targeted Drug Delivery With Insights From Mathematical Models.
    Sayoni Maitra Roy, Vrinda Garg, Sourav Barman, Chitrita Ghosh, Amit Ranjan Maity, Surya K Ghosh.
      Numerous strategies have been developed to treat cancer conventionally. Most importantly, chemotherapy shows its huge promise as a better treatment modality over others. Nonetheless, the very complex behavior of the tumor microenvironment frequently impedes successful drug delivery to the tumor sites that further demands very urgent and effective distribution mechanisms of anticancer drugs specifically to the tumor sites. Hence, targeted drug delivery to tumor sites has become a major challenge to the scientific community for cancer therapy by assuring drug effects to selective tumor tissue and overcoming undesired toxic side effects to the normal tissues. The application of nanotechnology to the drug delivery system pays heed to the design of nanomedicine for specific cell distribution. Aiming to limit the use of traditional strategies, the adequacy of drug-loaded nanocarriers (i.e., nanomedicine) proves worthwhile. After systemic blood circulation, a typical nanomedicine follows three levels of disposition to tumor cells in order to exhibit efficient pharmacological effects induced by the drug candidates residing within it. As a result, nanomedicine propounds the assurance towards the improved bioavailability of anticancer drug candidates, increased dose responses, and enhanced targeted efficiency towards delivery and distribution of effective therapeutic concentration, limiting toxic concentration. These aspects emanate the proficiency of drug delivery mechanisms. Understanding the potential tumor targeting barriers and limiting conditions for nanomedicine extravasation, tumor penetration, and final accumulation of the anticancer drug to tumor mass, experiments with in vivo animal models for nanomedicine screening are a key step before it reaches clinical translation. Although the study with animals is undoubtedly valuable, it has many associated ethical issues. Moreover, individual experiments are very expensive and take a longer time to conclude. To overcome these issues, nowadays, multicellular tumor spheroids are considered a promising in vitro model system that proposes better replication of in vivo tumor properties for the future development of new therapeutics. In this review, we will discuss how tumor spheroids could be used as an in vitro model system to screen nanomedicine used in targeted drug delivery, aiming for better therapeutic benefits. In addition, the recent proliferation of mathematical modeling approaches gives profound insight into the underlying physical principles and produces quantitative predictions. The hierarchical tumor structure is already well decorous to be treated mathematically. To study targeted drug delivery, mathematical modeling of tumor architecture, its growth, and the concentration gradient of oxygen are the points of prime focus. Not only are the quantitative models circumscribed to the spheroid, but also the role of modeling for the nanoparticle is equally inevitable. Abundant mathematical models have been set in motion for more elaborative and meticulous designing of nanomedicine, addressing the question regarding the objective of nanoparticle delivery to increase the concentration and the augmentative exposure of the therapeutic drug molecule to the core. Thus, to diffuse the dichotomy among the chemistry involved, biological data, and the underlying physics, the mathematical models play an indispensable role in assisting the experimentalist with further evaluation by providing the admissible quantitative approach that can be validated. This review will provide an overview of the targeted drug delivery mechanism for spheroid, using nanomedicine as an advantageous tool.
    Keywords:  in vitro cell culture; mathematical modeling; multicellular tumor spheroids; nanomedicine; tumor microenvironment; tumor penetration and accumulation; tumor-targeted drug delivery
    DOI:  https://doi.org/10.3389/fbioe.2021.785937
  92. Biomed Pharmacother. 2021 Dec 17. pii: S0753-3322(21)01329-9. [Epub ahead of print]146 112542
    Traditional Chinese medicine for precancerous lesions of gastric cancer: A review.
    Weichao Xu, Bolin Li, Miaochan Xu, Tianxiao Yang, Xinyu Hao.
      Gastric cancer (GC) is the fifth most common type of cancer and the third leading cause of death due to cancer worldwide. The gastric mucosa often undergoes many years of precancerous lesions of gastric cancer (PLGC) stages before progressing to gastric malignancy. Unfortunately, there are no effective Western drugs for patients with PLGC. In recent years, traditional Chinese medicine (TCM) has been proven effective in treating PLGC. Classical TCM formulas and chemical components isolated from some Chinese herbal medicines have been administered to treat PLGC, and the main advantage is their comprehensive intervention with multiple approaches and multiple targets. In this review, we focus on recent studies using TCM treatment for PLGC, including clinical observations and experimental research, with a focus on targets and mechanisms of drugs. This review provides some ideas and a theoretical basis for applying TCM to treat PLGC and prevent GC.
    Keywords:  Formulas; Pattern differentiation; Pharmacological mechanism; Precancerous lesions of gastric cancer; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.biopha.2021.112542
  93. Cancer Cell. 2021 Dec 20. pii: S1535-6108(21)00616-4. [Epub ahead of print]
    Functional precision oncology: Testing tumors with drugs to identify vulnerabilities and novel combinations.
    Anthony Letai, Patrick Bhola, Alana L Welm.
      Functional precision medicine is a strategy whereby live tumor cells from affected individuals are directly perturbed with drugs to provide immediately translatable, personalized information to guide therapy. The heterogeneity of human cancer has led to the realization that personalized approaches are needed to improve treatment outcomes. Precision oncology has traditionally used static features of the tumor to dictate which therapies should be used. Static features can include expression of key targets or genomic analysis of mutations to identify therapeutically targetable "drivers." Although a surprisingly small proportion of individuals derive clinical benefit from the static approach, functional precision medicine can provide additional information regarding tumor vulnerabilities. We discuss emerging technologies for functional precision medicine as well as limitations and challenges in using these assays in the clinical trials that will be necessary to determine whether functional precision medicine can improve outcomes and eventually become a standard tool in clinical oncology.
    Keywords:  Precision medicine; functional precision medicine; patient-derived models; precision oncology
    DOI:  https://doi.org/10.1016/j.ccell.2021.12.004
  94. Crit Rev Food Sci Nutr. 2021 Dec 21. 1-17
    A multifunctional study of naturally occurring pyrazines in biological systems; formation mechanisms, metabolism, food applications and functional properties.
    Nesrin M Fayek, Jianbo Xiao, Mohamed A Farag.
      Natural pyrazines, mainly methyl- or ethyl-substituted forms, are commonly applied as flavor ingredients in raw and roasted food. Meanwhile alkylpyrazines are used as food preservatives due to their effective antimicrobial action. These natural pyrazines are widely distributed in several biological systems such as plants, animals, and insects; each with respective physiological role. Besides, pyrazines are formed in food via thermal treatment and fermentation. This review presents the most comprehensive overview of pyrazines with correlation to their chemical structures and different applications with emphasis on their food applications. The major part deals with pyrazines generated in thermally treated food, reaction mechanisms highlighting factors and optimum conditions affecting their production. Additionally, the several metabolic reactions mediating for pyrazines metabolism in humans and excretion via the kidney are discussed and on context to their effects. Lastly, a review of the different techniques applied for pyrazines isolation, detection and quantitation is presented. The study provides future considerations and direction of research on this important dietary component and their applications. Pyrazines multifunctional chemistry is of value to the food sector, by presenting the best practices for their production whilst the detrimental effects are minimized.
    Keywords:  Detection; Pyrazines; food olfactory odors; formation; human metabolism; occurrence
    DOI:  https://doi.org/10.1080/10408398.2021.2017260
  95. Spectrochim Acta A Mol Biomol Spectrosc. 2021 Dec 11. pii: S1386-1425(21)01312-3. [Epub ahead of print]269 120735
    A vibrational in vitro approach to evaluate the potential of monoolein nanoparticles as isofuranodiene carrier in MDA-MB 231 breast cancer cell line: New insights from Infrared and Raman microspectroscopies.
    Valentina Notarstefano, Michela Pisani, Massimo Bramucci, Luana Quassinti, Filippo Maggi, Lisa Vaccari, Marco Parlapiano, Elisabetta Giorgini, Paola Astolfi.
      Isofuranodiene (IFD) is a sesquiterpene occurring in several plant species, which proved to have multiple anticancer activities. IFD has a lipophilic nature and, hence, a very low water solubility and a poor bioavailability; moreover, it is not stable, undergoing the "Cope rearrangement" to the less active curzerene. The use of appropriate delivery systems can thus be considered as a valid tool to enhance IFD bioavailability, solubility, stability and at the same time also to improve its intracellular uptake and pharmacological activity. Within this frame, monoolein (GMO) nanoparticles loaded with IFD were prepared and their enhanced anticancer activity, compared to pristine IFD, was assessed. In this study, for the first time, an in vitro Fourier Transform Infrared and Raman Microspectroscopy approaches were exploited to evaluate the effects of IFD, alone and loaded in GMO nanoparticles, on MDA-MB 231 breast cancer cell line. The anti-cancer effects of IFD were evidenced by both the spectroscopic techniques and discriminated from the GMO-induced changes in the culture environment; moreover, a synergistic effect of IFD and GMO administration can be envisaged by the experimental results.
    Keywords:  Chemometrics; Fourier Transform Infrared Microspectroscopy; Isofuranodiene; MDA-MB 231 cells; Monoolein nanoparticles; Raman Microspectroscopy
    DOI:  https://doi.org/10.1016/j.saa.2021.120735
  96. Toxicol Mech Methods. 2021 Dec 20. 1-42
    Aflatoxin B1: metabolism, toxicology, and its involvement in oxidative stress and cancer development.
    Weiya Cao, Pan Yu, KePeng Yang, Dongli Cao.
      Aflatoxins are a class of carcinogenic mycotoxins produced by Aspergillus fungi, which are widely distributed in nature. Aflatoxin B1 (AFB1) is the most toxic of these compounds and its metabolites have a variety of biological activities, including acute toxicity, teratogenicity, mutagenicity and carcinogenicity, which has been well-characterized to lead to the development of hepatocellular carcinoma (HCC) in humans and animals. This review focuses on the metabolism of AFB1, including epoxidation and DNA adduction, as it concerns the initiation of cancer and the underlying mechanisms. In addition to DNA adduction, inflammation and oxidative stress caused by AFB1 can also participate in the occurrence of cancer. Therefore, the main carcinogenic mechanism of AFB1 related ROS is summarized. This review also describes recent reports of AFB1 exposures in occupational settings. It is hoped that people will pay more attention to occupational health, in order to reduce the incidence of cancer caused by occupational exposure.
    Keywords:  Aflatoxin B1; Cancer; DNA adduct; Metabolism; Occupational Exposure; ROS
    DOI:  https://doi.org/10.1080/15376516.2021.2021339
  97. Molecules. 2021 Dec 17. pii: 7658. [Epub ahead of print]26(24):
    The Potential Role of Curcumin in Modulating the Master Antioxidant Pathway in Diabetic Hypoxia-Induced Complications.
    Somayyeh Ghareghomi, Mahdie Rahban, Zainab Moosavi-Movahedi, Mehran Habibi-Rezaei, Luciano Saso, Ali Akbar Moosavi-Movahedi.
      Oxidative stress is the leading player in the onset and development of various diseases. The Keap1-Nrf2 pathway is a pivotal antioxidant system that preserves the cells' redox balance. It decreases inflammation in which the nuclear trans-localization of Nrf2 as a transcription factor promotes various antioxidant responses in cells. Through some other directions and regulatory proteins, this pathway plays a fundamental role in preventing several diseases and reducing their complications. Regulation of the Nrf2 pathway occurs on transcriptional and post-transcriptional levels, and these regulations play a significant role in its activity. There is a subtle correlation between the Nrf2 pathway and the pivotal signaling pathways, including PI3 kinase/AKT/mTOR, NF-κB and HIF-1 factors. This demonstrates its role in the development of various diseases. Curcumin is a yellow polyphenolic compound from Curcuma longa with multiple bioactivities, including antioxidant, anti-inflammatory, anti-tumor, and anti-viral activities. Since hyperglycemia and increased reactive oxygen species (ROS) are the leading causes of common diabetic complications, reducing the generation of ROS can be a fundamental approach to dealing with these complications. Curcumin can be considered a potential treatment option by creating an efficient therapeutic to counteract ROS and reduce its detrimental effects. This review discusses Nrf2 pathway regulation at different levels and its correlation with other important pathways and proteins in the cell involved in the progression of diabetic complications and targeting these pathways by curcumin.
    Keywords:  Keap1-Nrf2; antioxidant enzymes; catalase; curcumin; diabetes; hypoxia-inducible factor 1 (HIF-1); oxidative stress
    DOI:  https://doi.org/10.3390/molecules26247658
  98. J Nanobiotechnology. 2021 Dec 19. 19(1): 428
    A molybdenum oxide-based degradable nanosheet for combined chemo-photothermal therapy to improve tumor immunosuppression and suppress distant tumors and lung metastases.
    Na Qiu, Xiaoye Yang, Yanan Zhang, Jicheng Zhang, Jianbo Ji, Yu Zhang, Xinru Kong, Yanwei Xi, Dongzhu Liu, Lei Ye, Guangxi Zhai.
      Molybdenum oxide (MoOx) nanosheets have drawn increasing attention for minimally invasive cancer treatments but still face great challenges, including complex modifications and the lack of efficient accumulation in tumor. In this work, a novel multifunctional degradable FA-BSA-PEG/MoOx nanosheet was fabricated (LA-PEG and FA-BSA dual modified MoOx): the synergistic effect of PEG and BSA endows the nanosheet with excellent stability and compatibility; the FA, a targeting ligand, facilitates the accumulation of nanosheets in the tumor. In addition, DTX, a model drug for breast cancer treatment, was loaded (76.49%, 1.5 times the carrier weight) in the nanosheets for in vitro and in vivo antitumor evaluation. The results revealed that the FA-BSA-PEG/MoOx@DTX nanosheets combined photothermal and chemotherapy could not only inhibit the primary tumor growth but also suppress the distant tumor growth (inhibition rate: 51.7%) and lung metastasis (inhibition rate: 93.6%), which is far more effective compared to the commercial Taxotere®. Exploration of the molecular mechanism showed that in vivo immune response induced an increase in positive immune responders, suppressed negative immune suppressors, and established an inflammatory tumor immune environment, which co-contributes towards effective suppression of tumor and lung metastasis. Our experiments demonstrated that this novel multifunctional nanosheet is a promising platform for combined chemo-photothermal therapy.
    Keywords:  Distant tumor and lung metastasis; Meliorate tumor immunosuppression; Molybdenum oxide nanosheet; Photothermal and chemotherapy
    DOI:  https://doi.org/10.1186/s12951-021-01162-2
  99. Antioxidants (Basel). 2021 Dec 16. pii: 2003. [Epub ahead of print]10(12):
    LC-MS/HRMS Analysis, Anti-Cancer, Anti-Enzymatic and Anti-Oxidant Effects of Boerhavia diffusa Extracts: A Potential Raw Material for Functional Applications.
    Kouadio Ibrahime Sinan, Uğur Akpulat, Afaf A Aldahish, Yasemin Celik Altunoglu, Mehmet Cengiz Baloğlu, Dimitrina Zheleva-Dimitrova, Reneta Gevrenova, Devina Lobine, Mohamad Fawzi Mahomoodally, Ouattara Katinan Etienne, Gokhan Zengin, Shafi Mahmud, Raffaele Capasso.
      Boerhavia diffusa is a great tropical plant and is widely used for various traditional purposes. In the present study, we examined the influence of solvents (dichloromethane, ethyl acetate, methanol and infusion (water)) on chemical composition and biological capabilities of B. diffusa. An UHPLC-HRMS method was used to determine the chemical characterization. The biological ability was examined for antioxidant, enzyme inhibitory and anti-cancer effects. To evaluate antioxidant effects, different chemical methods (ABTS, DPPH, CUPRAC, FRAP, metal chelating and phosphomolybdenum) were applied. With regard to enzyme inhibitory properties, cholinesterases, amylase, glucosidase and tyrosinase were used. The MDA-MB-231 breast cancer cell line was chosen to determine anticancer activity. Based on the UHPLC-HRMS analysis, 37 specialized metabolites were dereplicated and identified in the studied extracts. Results revealed the presence of 15 hydroxybenzoic, hydroxycinnamic, acylquinic acids, and their glycosides, one rotenoid, seven flavonoids, 12 fatty acids and two other glycosides. Among the tested extracts, the methanol extract showed a stronger antioxidant ability compared with other extracts. The methanol extract also showed the best inhibitory effects on tyrosinase and glucosidase. In the anti-cancer evaluation, the methanol extract showed stronger anticancer effects compared with water extract. In summary, our observations can contribute to the establishment of B. diffusa as a potential candidate for functional applications in the preparation.
    Keywords:  Boerhavia diffusa; anti-cancer; antioxidant; enzyme inhibition; flavonoids; functional applications
    DOI:  https://doi.org/10.3390/antiox10122003
  100. Langmuir. 2021 Dec 21.
    Synthesis of Photo, Oxidative, and Reductive Triple-Stimuli-Responsive Block Copolymer Micelles as Nanocarriers for Controlled Release.
    Qiong Guo, Jiangtao Liu, Hong Yang, Zhongli Lei.
      With the rapid development of nanotechnology, stimuli-responsive nanomaterials have provided an alternative for designing controllable drug delivery systems due to their spatiotemporally controllable properties. The environment of the human body is complex and cancer cells proliferate rapidly; the traditional nanocarriers could not release the loaded drugs sufficiently, and the release level of the drug is not sufficient for the requirement of treatment. Herein, a photoresponsive, glutathione, and reactive oxygen species block copolymer mPEG2k-ONB-SS-PO-mPEG2k is prepared by Cu(I)-catalyzed azide-alkyne cycloaddition click polymerization. The ο-nitrobenzyl groups, peroxalate ester bonds, disulfide bonds, and triazole units are regularly and repeatedly arranged in hydrophobic blocks. The photo, oxidative, and reductive responsive characteristics of the copolymers in different conditions were investigated by ultraviolet and visible spectrophotometry, dynamic light scattering, and transmission electron microscopy. Nile Red is encapsulated into the core of micelles as a model drug and exhibits the drug release behaviors in various environments. This research provides a way to design potential drug carriers and a promising platform for efficient intracellular drug delivery in cancer therapy.
    DOI:  https://doi.org/10.1021/acs.langmuir.1c02720
  101. Int J Nanomedicine. 2021 ;16 8049-8065
    Curcumin Nanoparticles Inhibiting Ferroptosis for the Enhanced Treatment of Intracerebral Hemorrhage.
    Cong Yang, Mengmeng Han, Ruoyu Li, Ligui Zhou, Ying Zhang, Lining Duan, Shiyu Su, Min Li, Qi Wang, Tongkai Chen, Yousheng Mo.
       Background: Intracerebral hemorrhage (ICH) is a form of severe stroke, the pathology of which is tied closely to a recently discovered form of programmed cell death known as ferroptosis. Curcumin (Cur) is a common phenolic compound extracted from the rhizome of Curcuma longa capable of hematoma volume and associated neurological damage in the context of ICH. Despite exhibiting therapeutic promise, the efficacy of Cur is challenged by its poor water solubility, limited oral bioavailability and inability to efficiently transit across the physiological barriers. Polymer-based nanoparticles (NPs) have widely been employed to aid in drug delivery efforts owing to their ideal biocompatibility and their ability to improve the bioavailability and pharmacokinetics of specific drugs of interest.
    Methods: In this study, we encapsulated Cur in NPs (Cur-NPs) and explored the effect of these Cur-NPs to enhance Cur delivery both in vitro and in vivo. Furthermore, we evaluated the anti-ferroptosis effect of Cur-NPs in ICH model mice and erastin-treated HT22 murine hippocampal cells.
    Results: The resultant Cur-NPs were spherical and exhibited a particle size of 127.31±2.73 nm, a PDI of 0.21±0.01 and a zeta potential of -0.25±0.02 mV. When applied to Madin Darby canine kidney (MDCK) cells in vitro, these Cur-NPs were nonspecifically internalized via multiple endocytic pathways, with plasma membrane microcapsules and clathrin-mediated uptake being the dominant mechanisms. Within cells, these NPs accumulated in lysosomes, endoplasmic reticulum and mitochondria. Cur-NPs were capable of passing through physiological barriers in a zebrafish model system. When administrated to C57BL/6 mice, they significantly improved Cur delivery to the brain. Most notably, when administered to ICH model mice, Cur-NPs achieved superior therapeutic outcomes relative to other treatments. In a final series of experiments, these Cur-NPs were shown to suppress erastin-induced ferroptosis in HT22 murine hippocampal cells.
    Conclusion: These Cur-NPs represent a promising means of improving Cur delivery to the brain and thereby better treating ICH.
    Keywords:  Intracerebral hemorrhage; blood-brain barrier; brain delivery; curcumin; ferroptosis; nanoparticles
    DOI:  https://doi.org/10.2147/IJN.S334965
  102. Adv Healthc Mater. 2021 Dec 22. e2101448
    Carbon Dots with Intrinsic Bioactivities for Photothermal Optical Coherence Tomography, tumor-specific Therapy and Postoperative Wound Management.
    Hao Liu, Luoqi Mo, Haolin Chen, Chao Chen, Jiayi Wu, Zhilie Tang, Zhouyi Guo, Chaofan Hu, Zhiming Liu.
      Carbon dots (CDs) have been considered as promising candidates with superior biocompatibilities for multimodel cancer theranostics. However, incorporation of exogenous components, such as targeting molecules and chemo/photo therapeutic drugs, are often required to improve the therapeutic efficacy. Herein, we propose an "all-in-one" CDs that exhibit intrinsic bioactivities for bioimaging, potent tumor therapy and postoperative management. The multifunctional CDs derived from gallic acid and tyrosine (GT-CDs) consist of a graphitized carbon core and N, O-rich functional groups, which endow them with a high near-infrared photothermal conversion efficiency of 33.9% and tumor-specific cytotoxicity, respectively. A new imaging modality, photothermal optical coherence tomography, is introduced using GT-CDs as the contrast agent, offering the micrometer-scale resolution three-dimensional tissue morphology of tumor. For cancer therapy, GT-CDs initiate the intracellular generation of reactive oxygen species in tumor cells but not normal cells, further induce the mitochondrial collapse and subsequent tumor cellular apoptosis. Combined with NIR photothermal treatment, synergistic antitumor therapy is achieved in vitro and in vivo. GT-CDs also promote the healing process of bacteria-contaminated skin wound, demonstrating their potential to prevent postoperative infection. The integrated theranostic strategy based on versatile GT-CDs supplies an alternative easy-to-handle pattern for disease management. This article is protected by copyright. All rights reserved.
    Keywords:  antibacterial activity; carbon dots; intrinsic bioactivity; photothermal optical coherence tomography; tumor-specific synergistic therapy
    DOI:  https://doi.org/10.1002/adhm.202101448
  103. Front Pharmacol. 2021 ;12 769929
    Liriopogons (Genera Ophiopogon and Liriope, Asparagaceae): A Critical Review of the Phytochemical and Pharmacological Research.
    Feiyi Lei, Caroline S Weckerle, Michael Heinrich.
      The closely related genera Liriope and Ophiopogon (Asparagaceae), collectively known in English as liriopogons, have similar therapeutic uses in treating cough, rheumatoid arthritis, and cleaning heat. The main aim of this review is to understand the current phytochemical and pharmacological knowledge including an assessment of the quality of the scientific evidence. A literature search was conducted in line with PRISMA guidelines, by retrieving available information up to 2020 from five online resources. The bioactive metabolites of liriopogons include steroidal saponins, flavonoids, polysaccharides, organic acids, phenols. Cardiovascular protective, anti-inflammatory, anti-diabetic, anti-oxidant, anti-cancer, neuroprotective, anti-viral, anti-acute myeloid leukemia and hepatoprotective effects have been at the center of attention. From a toxicological perspective Ophiopogon japonicus seems to be safe. Some problems with the quality of the pharmacological evidence stand out including the application of excessive dose level and methodological problems in the design. Additionally, a reasonable link between local/traditional uses and pharmacological assessment is often vague or not reflected in the text. Future researches on liriopogons are required to use rigorous scientific approaches in research on evidence-based natural products for the future benefits of patients.
    Keywords:  critical review; liriope; liriopogons; ophiopogon; pharmacology; phytochemistry
    DOI:  https://doi.org/10.3389/fphar.2021.769929
  104. Cancer Biol Med. 2021 Dec 22. pii: j.issn.2095-3941.2021.0504. [Epub ahead of print]
    Methods for monitoring cancer cell pyroptosis.
    Shuo Wang, Yuantong Liu, Lu Zhang, Zhijun Sun.
      Pyroptosis is a form of proinflammatory cell death that depends on the gasdermin family of proteins. The main features of pyroptosis are altered membrane permeability, cell swelling, membrane rupture, and the ability to mobilize a strong immune response. The relationship between pyroptosis and cancer has become a popular topic in immunological research. Multiple strategies for inducing pyroptosis in cancer cells have been developed for cancer therapy, including chemotherapy, small molecule drugs, and nanomedicines. In this review, we systematically discuss recent advances in research on the mechanisms of pyroptosis, and compare pyroptosis with apoptosis and necroptosis from several aspects. The development of various experimental systems has accompanied rapid progress in this field, but little consensus on monitoring pyroptosis is currently available. We focus on techniques commonly used to monitor pyroptosis, and describe future techniques that may be used to increase our knowledge in this field. Overall, the advancement of pyroptosis detection methods will help researchers to better investigate the relationships between pyroptosis and various cancers, and should provide insights into the use of these promising tools for cancer treatments.
    Keywords:  Pyroptosis; cancer immunotherapy; caspase; cell death; gasdermin
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0504
  105. Antioxidants (Basel). 2021 Nov 26. pii: 1894. [Epub ahead of print]10(12):
    The Role of Vitamin C in Cancer Prevention and Therapy: A Literature Review.
    Marcelo Villagran, Jorge Ferreira, Miquel Martorell, Lorena Mardones.
      Vitamin C is a water-soluble antioxidant associated with the prevention of the common cold and is also a cofactor of hydrolases that participate in the synthesis of collagen and catecholamines, and in the regulation of gene expression. In cancer, vitamin C is associated with prevention, progression, and treatment, due to its general properties or its role as a pro-oxidant at high concentration. This review explores the role of vitamin C in cancer clinical trials and the aspects to consider in future studies, such as plasmatic vitamin C and metabolite excretion recording, and metabolism and transport of vitamin C into cancer cells. The reviewed studies show that vitamin C intake from natural sources can prevent the development of pulmonary and breast cancer, and that vitamin C synergizes with gemcitabine and erlotinib in pancreatic cancer. In vitro assays reveal that vitamin C synergizes with DNA-methyl transferase inhibitors. However, vitamin C was not associated with cancer prevention in a Mendelian randomized study. In conclusion, the role of vitamin C in the prevention and treatment of cancer is still an ongoing area of research. It is necessary that new phase II and III clinical trials be performed to collect stronger evidence of the therapeutic role of vitamin C in cancer.
    Keywords:  ascorbic acid; cancer; clinical trial; vitamin C
    DOI:  https://doi.org/10.3390/antiox10121894
  106. Nanoscale. 2021 Dec 24.
    Z-Scheme heterostructures for glucose oxidase-sensitized radiocatalysis and starvation therapy of tumors.
    Ze Wang, Lu Wang, Shuwei Liu, Mengsi Zhang, Yunfeng Li, Li Rong, Yi Liu, Hao Zhang.
      Although many semiconductor heterojunctions have been prepared to promote radiation-generated exciton separation for radiocatalysis therapy (RCT), most of them inevitably sacrifice the redox ability of radiation-generated electrons and holes. Herein, we design and construct BiOI/Bi2S3@polydopamine nanosheets modified by amine-polyethylene glycol-folic acid and glucose oxidase for glucose oxidase-sensitized RCT and starvation therapy (ST) synergistic therapy of tumors. The unique Z-scheme energy level arrangement between BiOI and Bi2S3 can elevate the charge separation efficiency, as well as maximize the redox ability of radiation-generated electrons and holes, leading to the enhancement of the therapeutic efficacy of RCT. Since glucose oxidase can supply excess H2O2 for RCT to produce ˙OH on one hand, but efficiently cut off the energy supply of tumor cells via ST, on the other hand, our nanosheets exhibit superior tumor therapeutic efficacy to any single treatment benefiting from the cascade and synergy effects between RCT and ST.
    DOI:  https://doi.org/10.1039/d1nr07096g
  107. Curr Mol Pharmacol. 2021 Dec 17.
    Potential Natural Compounds for the Prevention and Treatment of Nonalcoholic Fatty Liver Disease: A Review on Molecular Mechanisms.
    Cheng Ma, Cheng Wang, Yafang Zhang, Honglin Zhou, Yunxia Li.
       BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, and there is no specific drug for its clinical treatment currently. In recent years, a large amount of literature has reported that many natural compounds extracted from traditional Chinese medicine (TCM) can improve NAFLD through various mechanisms. According to the latest reports, some emerging natural compounds have shown great potential to improve NAFLD but are seldom used clinically due to the lacking special research.
    PURPOSE: This paper aims to summarize the molecular mechanisms of the potential natural compounds on improving NAFLD, thus providing a direction and basis for further research on the pathogenesis of NAFLD and the development of effective drugs for the prevention and treatment of NAFLD.
    METHODS: By searching various online databases, such as Web of Science, SciFinder, PubMed, and CNKI, NAFLD and these natural compounds were used as the keywords for detailed literature retrieval.
    RESULTS: The pathogenesis of NAFLD and the molecular mechanisms of the potential natural compounds on improving NAFLD have been reviewed.
    CONCLUSION: Many natural compounds from traditional Chinese medicine have a good prospect in the treatment of NAFLD, which can serve as a direction for the development of anti-NAFLD drugs in the future.
    Keywords:  "Multiple hit" theory; Molecular mechanisms; Natural compounds; Nonalcoholic fatty liver disease; Pathogenesis; Traditional Chinese medicine
    DOI:  https://doi.org/10.2174/1874467215666211217120448
  108. Front Oncol. 2021 ;11 772305
    Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer.
    Jordan A Harry, Mark L Ormiston.
      Breast cancer is the most common cancer affecting women and is the second leading cause of cancer related death worldwide. Angiogenesis, the process of new blood vessel development from pre-existing vasculature, has been implicated in the growth, progression, and metastasis of cancer. Tumor angiogenesis has been explored as a key therapeutic target for decades, as the blockade of this process holds the potential to reduce the oxygen and nutrient supplies that are required for tumor growth. However, many existing anti-angiogenic approaches, such as those targeting Vascular Endothelial Growth Factor, Notch, and Angiopoietin signaling, have been associated with severe side-effects, limited survival advantage, and enhanced cancer regrowth rates. To address these setbacks, alternative pathways involved in the regulation of tumor angiogenesis are being explored, including those involving Bone Morphogenetic Protein-9 signaling, the Sonic Hedgehog pathway, Cyclooxygenase-2, p38-mitogen-activated protein kinase, and Chemokine Ligand 18. This review article will introduce the concept of tumor angiogenesis in the context of breast cancer, followed by an overview of current anti-angiogenic therapies, associated resistance mechanisms and novel therapeutic targets.
    Keywords:  angiogenesis; bone morphogenetic protein 9; breast cancer; notch signaling; vascular endothelial growth factor
    DOI:  https://doi.org/10.3389/fonc.2021.772305
  109. Biomolecules. 2021 Dec 04. pii: 1830. [Epub ahead of print]11(12):
    Diet Impact on Obesity beyond Calories and Trefoil Factor Family 2 (TFF2) as an Illustration: Metabolic Implications and Potential Applications.
    Abdelaziz Ghanemi, Mayumi Yoshioka, Jonny St-Amand.
      Obesity is a health problem with increasing impacts on public health, economy and even social life. In order to reestablish the energy balance, obesity management focuses mainly on two pillars; exercise and diet. Beyond the contribution to the caloric intake, the diet nutrients and composition govern a variety of properties. This includes the energy balance-independent properties and the indirect metabolic effects. Whereas the energy balance-independent properties are close to "pharmacological" effects and include effects such as antioxidant and anti-inflammatory, the indirect metabolic effects represent the contribution a diet can have on energy metabolism beyond the caloric contribution itself, which include the food intake control and metabolic changes. As an illustration, we also described the metabolic implication and hypothetical pathways of the high-fat diet-induced gene Trefoil Factor Family 2. The properties the diet has can have a variety of applications mainly in pharmacology and nutrition and further explore the "pharmacologically" active food towards potential therapeutic applications.
    Keywords:  calories; diet; energy metabolism; high-fat diet; obesity; trefoil factor family member 2
    DOI:  https://doi.org/10.3390/biom11121830
  110. Acta Biomater. 2021 Dec 16. pii: S1742-7061(21)00821-7. [Epub ahead of print]
    Tumor Microcalcification-mediated Relay Drug Delivery for Photodynamic Immunotherapy of Breast Cancer.
    Hui Jian, Xingbo Wang, PanPan Song, Xiaqing Wu, Runxiao Zheng, Yanjing Wang, Haiyuan Zhang.
      Spatiotemporal targeting of tumor-associated macrophages (TAMs) and tumor cells is emerging as a promising strategy for tumor therapy. Tumor microcalcifications that specifically bind to bisphosphonates are potentially used to design efficient relay drug delivery nanosystems to achieve spatiotemporal drug modulation. Here, we developed manganese dioxide (MnO2)-embedded and LyP-1 peptide-labeled liposomal nanoparticles (NPs) for photodynamic immunotherapy of breast cancer; zoledronic acid (Zol) was encapsulated in the hydrophilic cavity of liposomes, and a hydrophobic photosensitizer (IR780) was embedded in the phospholipid bilayer of liposomes. These Lipo Zol/IR NPs generated O2 bubbles through MnO2 in response to H2O2 in the tumor microenvironment, leading to the degradation of the liposomal membrane, which triggered the release of Zol and provided O2 for photodynamic therapy. The released Zol attached to microcalcifications and was selectively phagocytosed by TAMs, leading to the induction of death or repolarization of TAMs from the immunosuppressive M2 phenotype to the immunostimulatory M1 phenotype. The remaining liposomal fragments embedded with IR780 then preferentially targeted tumor cells through LyP-1 peptide and produced abundant reactive oxygen species (ROS) under near infrared (NIR) laser irradiation, resulting in the death of tumor cells and mild immune activation. All in vitro and in vivo studies demonstrated the effective photodynamic and immunoregulatory performance of Lipo Zol/IR NPs. STATEMENT OF SIGNIFICANCE: : Spatiotemporal targeting of tumor-associated macrophages (TAMs) and tumor cells remains a challenge in tumor photodynamic immunotherapy for promoting synergy and reducing side effects. Here, we developed tumor microcalcification-mediated relay drug delivery nanoliposomes for breast cancer therapy. H2O2 in the tumor microenvironment (TME) triggers the breakage of nanoliposomes, thereby causing the separation of zoledronic acid (Zol) and the photosensitizer IR780 and allowing them to perform their respective functions. Microcalcifications enable Zol to target TAMs, resulting in immunomodulation. LyP-1 guides IR780 to target tumor cells for PDT with adequate O2 supply. These nanoliposomes enable precise spatiotemporal targeting of different types of cells in the TME and promote the synergy between immunotherapy and PDT while ensuring the effectiveness of both methods.
    Keywords:  microcalcification; photodynamic immunotherapy; relay drug delivery; repolarization; tumor-associated macrophage (TAM)
    DOI:  https://doi.org/10.1016/j.actbio.2021.12.014
  111. Molecules. 2021 Dec 09. pii: 7453. [Epub ahead of print]26(24):
    Natural Peptides Inducing Cancer Cell Death: Mechanisms and Properties of Specific Candidates for Cancer Therapeutics.
    Plinio A Trinidad-Calderón, Carlos Daniel Varela-Chinchilla, Silverio García-Lara.
      Nowadays, cancer has become the second highest leading cause of death, and it is expected to continue to affect the population in forthcoming years. Additionally, treatment options will become less accessible to the public as cases continue to grow and disease mechanisms expand. Hence, specific candidates with confirmed anticancer effects are required to develop new drugs. Among the novel therapeutic options, proteins are considered a relevant source, given that they have bioactive peptides encrypted within their sequences. These bioactive peptides, which are molecules consisting of 2-50 amino acids, have specific activities when administered, producing anticancer effects. Current databases report the effects of peptides. However, uncertainty is found when their molecular mechanisms are investigated. Furthermore, analyses addressing their interaction networks or their directly implicated mechanisms are needed to elucidate their effects on cancer cells entirely. Therefore, relevant peptides considered as candidates for cancer therapeutics with specific sequences and known anticancer mechanisms were accurately reviewed. Likewise, those features which turn certain peptides into candidates and the mechanisms by which peptides mediate tumor cell death were highlighted. This information will make robust the knowledge of these candidate peptides with recognized mechanisms and enhance their non-toxic capacity in relation to healthy cells and further avoid cell resistance.
    Keywords:  apoptosis; cancer; cell; death; mechanism; membrane; model; peptide; therapeutics
    DOI:  https://doi.org/10.3390/molecules26247453
  112. Small Methods. 2021 Sep;5(9): e2100581
    A Mitochondrial Oxidative Stress Amplifier to Overcome Hypoxia Resistance for Enhanced Photodynamic Therapy.
    Ping Dong, Jialing Hu, Shuyi Yu, Yizhuo Zhou, Tianhui Shi, Yun Zhao, Xiuyuan Wang, Xiaoqing Liu.
      Hypoxia-induced resistance to tumor treatment restricts further development of photodynamic therapy. Instead of simple reoxygenation to relieve hypoxia in traditional therapeutic approaches, a mitochondria-targeted reactive oxygen species (ROS) amplifier is constructed to reverse hypoxia resistance and enhance tumor sensitivity to hypoxia-resistant photodynamic therapy. Mesoporous silica nanoparticles are modified with triphenylphosphine to enhance its blood circulation and endow it with mitochondria-targeted specificity. α-Tocopherol succinate and indocyanine green are loaded in mitochondria-targeted mesoporous silica nanoparticles to reduce innate oxygen consumption by blocking mitochondrial respiration chain, leading to endogenous mitochondrial ROS burst and imaging-guided photodynamic therapy. This mitochondria-targeted oxidative stress amplifier not only disrupts mitochondrial redox homeostasis and triggers long-term high oxidative stress but also makes tumor more sensitive to hypoxia-resistant photodynamic therapy. The imaging-guided ROS amplifier confirms the feasibility and effectiveness of both in vitro and in vivo anticancer performance, suggesting a promising clinical strategy in hypoxia-related tumor treatment.
    Keywords:  hypoxia resistance; mitochondria; photodynamic therapy; reactive oxygen species burst; respiration inhibition
    DOI:  https://doi.org/10.1002/smtd.202100581
  113. Cancer Epidemiol Biomarkers Prev. 2021 Dec 21. pii: cebp.EPI-21-0678-E.2021. [Epub ahead of print]
    Energy balance-related factors and risk of colorectal cancer expressing different levels of proteins involved in the Warburg-effect.
    Josien C A Jenniskens, Kelly Offermans, Colinda Cjm Simons, Iryna Samarska, Gregorio E Fazzi, Kim M Smits, Leo J Schouten, Matty P Weijenberg, Heike I Grabsch, Piet A van den Brandt.
       BACKGROUND: Energy balance-related factors (BMI, waist circumference, physical activity) have been associated with colorectal cancer (CRC) risk. Warburg-effect activation via PI3K/Akt-signaling is one of the proposed mechanisms. We investigated whether energy balance-related factors were associated with risk of Warburg-subtypes in CRC.
    METHODS: We investigated this using immunohistochemistry for six proteins involved in the Warburg-effect (LDHA, GLUT1, MCT4, PKM2, P53, PTEN) on tissue microarrays of 2,399 incident CRC cases from the prospective Netherlands Cohort Study (NLCS; ntotal=120,852; nsubcohort=5000; aged 55-69 in 1986; 20.3 years follow-up). Data analyses included 3,911 subcohort members and 1,972 CRC cases with complete covariate data. Expression levels of all proteins were combined into a pathway-based sum score and categorized into three "Warburg-subtypes" (Warburg-low/-moderate/-high). Multivariable Cox-regression analyses were used to estimate associations of BMI, clothing-size (waist circumference proxy), and physical activity with Warburg-subtypes in CRC.
    RESULTS: BMI and clothing-size were positively associated with Warburg-moderate and Warburg-high colon cancer risk in men (P-heterogeneity=0.192). In women, clothing-size was positively associated with Warburg-low and Warburg-high colon cancer (P-heterogeneity=0.005). Non-occupational physical activity was inversely associated with Warburg-low and Warburg-moderate colon cancer in women (P-heterogeneity=0.045), but positively associated with Warburg-high rectal cancer in men (P-heterogeneity=0.089).
    CONCLUSIONS: The Warburg-effect might be involved in associations between adiposity and colon cancer risk, though additional mechanisms could be at play in women as well. The inverse association between physical activity and colon cancer might be explained by mechanisms other than the Warburg-effect.
    IMPACT: Further research is needed to reproduce these results, and investigate possible additional mechanisms.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-21-0678
  114. Cancer Lett. 2021 Dec 16. pii: S0304-3835(21)00627-3. [Epub ahead of print]
    Drug repositioning: Using psychotropic drugs for the treatment of glioma.
    Fangting You, Caiyi Zhang, Xiaoxiao Liu, Daofei Ji, Tong Zhang, Rutong Yu, Shangfeng Gao.
      Psychotropic drugs can penetrate the blood-brain barrier and regulate the levels of neurotransmitters and neuromodulators such as γ-aminobutyric acid, glutamate, serotonin, dopamine, and norepinephrine in the brain, and thus influence neuronal activity. Neuronal activity in the tumor microenvironment can promote the growth and expansion of glioma. There is increasing evidence that in addition to their use in the treatment of mental disorders, antipsychotic, antidepressant, and mood-stabilizing drugs have clinical potential for cancer therapy. These drugs have been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasion/migration or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. In this review, we summarize findings from preclinical and clinical studies investigating the use of antipsychotics, antidepressants, and mood stabilizers in the treatment of various types of cancer, with a focus on glioma; and discuss their presumed antitumor mechanisms. The existing evidence indicates that psychotropic drugs with established pharmacologic and safety profiles can be repurposed as anticancer agents, thus providing new options for the treatment of glioma.
    Keywords:  Antidepressant drug; Antipsychotic drug; Glioblastoma; Mood stabilizer
    DOI:  https://doi.org/10.1016/j.canlet.2021.12.014
  115. Front Public Health. 2021 ;9 777160
    Carbon Ion Radiotherapy Evokes a Metabolic Reprogramming and Individualized Response in Prostate Cancer.
    Renli Ning, Yulei Pei, Ping Li, Wei Hu, Yong Deng, Zhengshan Hong, Yun Sun, Qing Zhang, Xiaomao Guo.
      Introduction: Carbon ion radiotherapy (CIRT) is a novel treatment for prostate cancer (PCa). However, the underlying mechanism for the individualized response to CIRT is still not clear. Metabolic reprogramming is essential for tumor growth and proliferation. Although changes in metabolite profiles have been detected in patients with cancer treated with photon radiotherapy, there is limited data regarding CIRT-induced metabolic changes in PCa. Therefore, the study aimed to investigate the impact of metabolic reprogramming on individualized response to CIRT in patients with PCa. Materials and Methods: Urine samples were collected from pathologically confirmed patients with PCa before and after CIRT. A UPLC-MS/MS system was used for metabolite detection. XCMS online, MetDNA, and MS-DIAL were used for peak detection and identification of metabolites. Statistical analysis and metabolic pathway analysis were performed on MetaboAnalyst. Results: A total of 1,701 metabolites were monitored in this research. Principal component analysis (PCA) revealed a change in the patient's urine metabolite profiles following CIRT. Thirty-five metabolites were significantly altered, with the majority of them being amino acids. The arginine biosynthesis and histidine metabolism pathways were the most significantly altered pathways. Hierarchical cluster analysis (HCA) showed that after CIRT, the patients could be clustered into two groups according to their metabolite profiles. The arginine biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis pathways are the most significantly discriminated pathways. Conclusion: Our preliminary findings indicate that metabolic reprogramming and inhibition are important mechanisms involved in response to CIRT in patients with PCa. Therefore, changes in urine metabolites could be used to timely assess the individualized response to CIRT.
    Keywords:  carbon ion radiotherapy; individualized response; metabolic reprogramming; metabolite profiles; metabolites; prostate cancer
    DOI:  https://doi.org/10.3389/fpubh.2021.777160
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