bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–11–28
eighty papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. An Asp to Strike Out Cancer? Therapeutic Possibilities Arising from Aspartate's Emerging Roles in Cell Proliferation and Survival.
  2. Mitochondrial Redox Metabolism: The Epicenter of Metabolism during Cancer Progression.
  3. Cancer Stem Cells: Metabolic Characterization for Targeted Cancer Therapy.
  4. Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis.
  5. Effects and mechanisms of dietary bioactive compounds on breast cancer prevention.
  6. Microtubule-Based Mitochondrial Dynamics as a Valuable Therapeutic Target in Cancer.
  7. Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy.
  8. Succinate receptor 1 inhibits mitochondrial respiration in cancer cells addicted to glutamine.
  9. The mechanisms and therapeutic targets of ferroptosis in cancer.
  10. Nanoparticles for Ferroptosis Therapy in Cancer.
  11. Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
  12. Metallic Nanoparticle-Mediated Immune Cell Regulation and Advanced Cancer Immunotherapy.
  13. Ferroptosis: Cancer Stem Cells Rely on Iron until "to Die for" It.
  14. Oncogenic KRAS: Signaling and Drug Resistance.
  15. Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach.
  16. Understanding the Role of Autophagy in Cancer Formation and Progression Is a Real Opportunity to Treat and Cure Human Cancers.
  17. Targeting ferroptosis-based cancer therapy using nanomaterials: strategies and applications.
  18. Immunomodulatory Effects of a Concoction of Natural Bioactive Compounds-Mechanistic Insights.
  19. New Insights into Curcumin- and Resveratrol-Mediated Anti-Cancer Effects.
  20. Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets.
  21. Mechanisms and pharmacological applications of ferroptosis: a narrative review.
  22. Targeting Engineered Nanoparticles for Breast Cancer Therapy.
  23. Targeting AMPK Signaling by Dietary Polyphenols in Cancer Prevention.
  24. Resveratrol Targets a Variety of Oncogenic and Oncosuppressive Signaling for Ovarian Cancer Prevention and Treatment.
  25. Chloroquine Induces ROS-mediated Macrophage Migration Inhibitory Factor Secretion and Epithelial to Mesenchymal Transition in ER-positive Breast Cancer Cell Lines.
  26. Phytochemicals as an Alternative or Integrative Option, in Conjunction with Conventional Treatments for Hepatocellular Carcinoma.
  27. Nanoparticle Systems for Cancer Phototherapy: An Overview.
  28. Mechanisms, Diagnosis and Treatment of Bone Metastases.
  29. HuaChanSu suppresses tumor growth and interferes with glucose metabolism in hepatocellular carcinoma cells by restraining Hexokinase-2.
  30. The double faced role of xanthine oxidoreductase in cancer.
  31. Metabolic Fuel for Epigenetic: Nuclear Production Meets Local Consumption.
  32. Current Strategies for Cancer Cell-Derived Extracellular Vesicles for Cancer Therapy.
  33. Meta-Inflammation and Metabolic Reprogramming of Macrophages in Diabetes and Obesity: The Importance of Metabolites.
  34. Nanoparticle-Mediated Delivery Systems in Photodynamic Therapy of Colorectal Cancer.
  35. The Role of Aldehyde Oxidase in the Metabolic Clearance of Substituted Benzothiazoles.
  36. Context Matters-Why We Need to Change From a One Size Fits all Approach to Made-to-Measure Therapies for Individual Patients With Pancreatic Cancer.
  37. Gallic acid: a dietary polyphenol that exhibits anti-neoplastic activities by modulating multiple oncogenic targets.
  38. The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies.
  39. Antitumor Immune Response Triggered by Metal-Based Photosensitizers for Photodynamic Therapy: Where Are We?
  40. Metabolomics-Microbiome Crosstalk in the Breast Cancer Microenvironment.
  41. Rutin (Bioflavonoid) as Cell Signaling Pathway Modulator: Prospects in Treatment and Chemoprevention.
  42. Polyphenols, the Healthy Brand of Olive Oil: Insights and Perspectives.
  43. Natural Products for the Management of Castration-Resistant Prostate Cancer: Special Focus on Nanoparticles Based Studies.
  44. Vitamins as Possible Cancer Biomarkers: Significance and Limitations.
  45. Application of chitosan modified nanocarriers in breast cancer.
  46. A Glutathione Activatable Photosensitizer for Combined Photodynamic and Gas Therapy under Red Light Irradiation.
  47. Per- and Polyfluoroalkyl Substance Exposure Combined with High-Fat Diet Supports Prostate Cancer Progression.
  48. Vitamin D-Mediated Anti-cancer Activity Involves Iron Homeostatic Balance Disruption and Oxidative Stress Induction in Breast Cancer.
  49. Halophilic Carotenoids and Breast Cancer: From Salt Marshes to Biomedicine.
  50. The mTOR Pathway in Pluripotent Stem Cells: Lessons for Understanding Cancer Cell Dormancy.
  51. Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective.
  52. Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction.
  53. Decanoic Acid Stimulates Autophagy in D. discoideum.
  54. Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy.
  55. Recent Advancement in Chitosan-Based Nanoparticles for Improved Oral Bioavailability and Bioactivity of Phytochemicals: Challenges and Perspectives.
  56. Targeted Therapies in Cancer: To Be or Not to Be, Selective.
  57. Ketamine suppresses proliferation and induces ferroptosis and apoptosis of breast cancer cells by targeting KAT5/GPX4 axis.
  58. Kaempferol, Myricetin and Fisetin in Prostate and Bladder Cancer: A Systematic Review of the Literature.
  59. Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence.
  60. Advances in glioma-associated oncogene (GLI) inhibitors for cancer therapy.
  61. Stimuli Responsive Nitric Oxide-Based Nanomedicine for Synergistic Therapy.
  62. Multiple Antitumor Molecular Mechanisms Are Activated by a Fully Synthetic and Stabilized Pharmaceutical Product Delivering the Active Compound Sulforaphane (SFX-01) in Preclinical Model of Human Glioblastoma.
  63. Urinary Metabolic Markers of Bladder Cancer: A Reflection of the Tumor or the Response of the Body?
  64. Chronobiology and Metabolism: Is Ketogenic Diet Able to Influence Circadian Rhythm?
  65. Target Nanoparticles against Pancreatic Cancer: Fewer Side Effects in Therapy.
  66. Selective cytotoxicity mechanisms and biodistribution of diamond nanoparticles on the skin cancer in C57 mouse.
  67. Bisdemethoxycurcumin Promotes Apoptosis and Inhibits the Epithelial-Mesenchymal Transition through the Inhibition of the G-Protein-Coupled Receptor 161/Mammalian Target of Rapamycin Signaling Pathway in Triple Negative Breast Cancer Cells.
  68. Ten Reasons Why People With Down Syndrome are Protected From the Development of Most Solid Tumors -A Review.
  69. Role of Survivin in Bladder Cancer: Issues to Be Overcome When Designing an Efficient Dual Nano-Therapy.
  70. Natural Products Induce Lysosomal Membrane Permeabilization as an Anticancer Strategy.
  71. Onco-Preventive and Chemo-Protective Effects of Apple Bioactive Compounds.
  72. Treatment of HT29 Human Colorectal Cancer Cell Line with Nanocarrier-Encapsulated Camptothecin Reveals Histone Modifier Genes in the Wnt Signaling Pathway as Important Molecular Cues for Colon Cancer Targeting.
  73. Targeting Hypoxia: Revival of Old Remedies.
  74. Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms.
  75. Iron Oxide Nanoparticle-Based Hyperthermia as a Treatment Option in Various Gastrointestinal Malignancies.
  76. Single nanosheet can sustainably generate oxygen and inhibit respiration simultaneously in cancer cells.
  77. Ethoxyquin Inhibits the Progression of Murine Ehrlich Ascites Carcinoma through the Inhibition of Autophagy and LDH.
  78. Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy.
  79. Tetrahydrobiopterin in cell function and death mechanisms.
  80. Research Techniques Made Simple: Profiling Cellular Energy Metabolism.
  1. Biomolecules. 2021 Nov 10. pii: 1666. [Epub ahead of print]11(11):
    An Asp to Strike Out Cancer? Therapeutic Possibilities Arising from Aspartate's Emerging Roles in Cell Proliferation and Survival.
    Iiro Taneli Helenius, Hanumantha Rao Madala, Jing-Ruey Joanna Yeh.
      A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable for cell proliferation. Moreover, the malate-aspartate shuttle plays a key role in redox balance, and a deficit in aspartate can lead to oxidative stress. It is now recognized that aspartate biosynthesis is largely governed by mitochondrial metabolism, including respiration and glutaminolysis in cancer cells. Therefore, under conditions that suppress mitochondrial metabolism, including mutations, hypoxia, or chemical inhibitors, aspartate can become a limiting factor for tumor growth and cancer cell survival. Notably, aspartate availability has been associated with sensitivity or resistance to various therapeutics that are presently in the clinic or in clinical trials, arguing for a critical need for more effective aspartate-targeting approaches. In this review, we present current knowledge of the metabolic roles of aspartate in cancer cells and describe how cancer cells maintain aspartate levels under different metabolic states. We also highlight several promising aspartate level-modulating agents that are currently under investigation.
    Keywords:  GOT1; alpha-ketoglutarate; asparagine; aspartate; cancer metabolism; glutaminase; hypoxia; mitochondrial DNA mutation; mitochondrial respiration; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/biom11111666
  2. Antioxidants (Basel). 2021 Nov 19. pii: 1838. [Epub ahead of print]10(11):
    Mitochondrial Redox Metabolism: The Epicenter of Metabolism during Cancer Progression.
    Feroza K Choudhury.
      Mitochondrial redox metabolism is the central component in the cellular metabolic landscape, where anabolic and catabolic pathways are reprogrammed to maintain optimum redox homeostasis. During different stages of cancer, the mitochondrial redox status plays an active role in navigating cancer cells' progression and regulating metabolic adaptation according to the constraints of each stage. Mitochondrial reactive oxygen species (ROS) accumulation induces malignant transformation. Once vigorous cell proliferation renders the core of the solid tumor hypoxic, the mitochondrial electron transport chain mediates ROS signaling for bringing about cellular adaptation to hypoxia. Highly aggressive cells are selected in this process, which are capable of progressing through the enhanced oxidative stress encountered during different stages of metastasis for distant colonization. Mitochondrial oxidative metabolism is suppressed to lower ROS generation, and the overall cellular metabolism is reprogrammed to maintain the optimum NADPH level in the mitochondria required for redox homeostasis. After reaching the distant organ, the intrinsic metabolic limitations of that organ dictate the success of colonization and flexibility of the mitochondrial metabolism of cancer cells plays a pivotal role in their adaptation to the new environment.
    Keywords:  ROS signaling; distant colonization; metastasis; mitochondrial redox metabolism; tumor development
    DOI:  https://doi.org/10.3390/antiox10111838
  3. Front Oncol. 2021 ;11 756888
    Cancer Stem Cells: Metabolic Characterization for Targeted Cancer Therapy.
    Jasmeet Kaur, Shalmoli Bhattacharyya.
      The subpopulation of cancer stem cells (CSCs) within tumor bulk are known for tumor recurrence and metastasis. CSCs show intrinsic resistance to conventional therapies and phenotypic plasticity within the tumor, which make these a difficult target for conventional therapies. CSCs have different metabolic phenotypes based on their needs as compared to the bulk cancer cells. CSCs show metabolic plasticity and constantly alter their metabolic state between glycolysis and oxidative metabolism (OXPHOS) to adapt to scarcity of nutrients and therapeutic stress. The metabolic characteristics of CSCs are distinct compared to non-CSCs and thus provide an opportunity to devise more effective strategies to target CSCs. Mechanism for metabolic switch in CSCs is still unravelled, however existing evidence suggests that tumor microenvironment affects the metabolic phenotype of cancer cells. Understanding CSCs metabolism may help in discovering new and effective clinical targets to prevent cancer relapse and metastasis. This review summarises the current knowledge of CSCs metabolism and highlights the potential targeted treatment strategies.
    Keywords:  OxPhos; cancer stem cell; glucose; glutamine; metabolism
    DOI:  https://doi.org/10.3389/fonc.2021.756888
  4. Amino Acids. 2021 Nov 26.
    Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis.
    James M Phang.
      In the 35 years since the introduction of the "proline cycle", its relevance to human tumors has been widely established. These connections are based on a variety of mechanisms discovered by many laboratories and have stimulated the search for small molecule inhibitors to treat cancer or metastases. In addition, the multi-layered connections of the proline cycle and the role of proline and hydroxyproline in collagen provide an important regulatory link between the extracellular matrix and metabolism.
    Keywords:  Cancer therapy; Extracellular matrix; Metabolic reprogramming; Nucleotides; Redox
    DOI:  https://doi.org/10.1007/s00726-021-03103-7
  5. Pharmacol Res. 2021 Nov 21. pii: S1043-6618(21)00558-2. [Epub ahead of print] 105974
    Effects and mechanisms of dietary bioactive compounds on breast cancer prevention.
    Ganesan Kumar, Bing Du, Jianping Chen.
      Breast cancer (BC) is the most often diagnosed cancer among females globally and has become an increasing global health issue over the last decades. Despite the substantial improvement in screening methods for initial diagnosis, effective therapy remains lacking. Still, there has been high recurrence and disease progression after treatment of surgery, endocrine therapy, chemotherapy, and radiotherapy. Considering this view, there is a crucial requirement to develop safe, freely accessible, and effective anticancer therapy for BC. The dietary bioactive compounds as auspicious anticancer agents have been recognized to be active and their implications in the treatment of BC with negligible side effects. Hence, this review focused on various dietary bioactive compounds as potential therapeutic agents in the prevention and treatment of BC with the mechanisms of action. Bioactive compounds have chemo-preventive properties as they inhibit the proliferation of cancer cells, downregulate the expression of estrogen receptors, and cell cycle arrest by inducing apoptotic settings in tumor cells. Therapeutic drugs or natural compounds generally incorporate engineered nanoparticles with ideal sizes, shapes, and enhance their solubility, circulatory half-life, and biodistribution. All data of in vitro, in vivo, and clinical studies of dietary bioactive compounds and their impact on BC were collected from Science Direct, PubMed, and Google Scholar. The data of chemopreventive and anticancer activity of dietary bioactive compounds were collected and orchestrated in a suitable place in the review. These shreds of data will be extremely beneficial to recognize a series of additional diet-derived bioactive compounds to treat BC with the lowest side effects.
    Keywords:  Dietary bioactive compounds; breast cancer; in vivo and clinical studies; mechanism; therapeutic agents
    DOI:  https://doi.org/10.1016/j.phrs.2021.105974
  6. Cancers (Basel). 2021 Nov 19. pii: 5812. [Epub ahead of print]13(22):
    Microtubule-Based Mitochondrial Dynamics as a Valuable Therapeutic Target in Cancer.
    Rosa Vona, Anna Maria Mileo, Paola Matarrese.
      Mitochondria constitute an ever-reorganizing dynamic network that plays a key role in several fundamental cellular functions, including the regulation of metabolism, energy production, calcium homeostasis, production of reactive oxygen species, and programmed cell death. Each of these activities can be found to be impaired in cancer cells. It has been reported that mitochondrial dynamics are actively involved in both tumorigenesis and metabolic plasticity, allowing cancer cells to adapt to unfavorable environmental conditions and, thus, contributing to tumor progression. The mitochondrial dynamics include fusion, fragmentation, intracellular trafficking responsible for redistributing the organelle within the cell, biogenesis, and mitophagy. Although the mitochondrial dynamics are driven by the cytoskeleton-particularly by the microtubules and the microtubule-associated motor proteins dynein and kinesin-the molecular mechanisms regulating these complex processes are not yet fully understood. More recently, an exchange of mitochondria between stromal and cancer cells has also been described. The advantage of mitochondrial transfer in tumor cells results in benefits to cell survival, proliferation, and spreading. Therefore, understanding the molecular mechanisms that regulate mitochondrial trafficking can potentially be important for identifying new molecular targets in cancer therapy to interfere specifically with tumor dissemination processes.
    Keywords:  cancer bioenergetics; microtubules; mitochondria dynamics; mitophagy; tunneling nanotubes
    DOI:  https://doi.org/10.3390/cancers13225812
  7. Bioact Mater. 2022 Mar;9 15-28
    Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy.
    Longfa Kou, Xinyu Jiang, Yingying Tang, Xing Xia, Yingtao Li, Aimin Cai, Hailun Zheng, Hailin Zhang, Vadivel Ganapathy, Qing Yao, Ruijie Chen.
      Reprogramed cellular metabolism is one of the most significant hallmarks of cancer. All cancer cells exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. The resultant enhanced availability of amino acids supports the reprogramed metabolic pathways and fuels the malignant growth and metastasis of cancers by providing energy and critical metabolic intermediates, facilitating anabolism, and activating signaling networks related to cell proliferation and growth. Therefore, pharmacologic blockade of amino acid entry into cancer cells is likely to have a detrimental effect on cancer cell growth. Here we developed a nanoplatform (LJ@Trp-NPs) to therapeutically target two transporters, SLC6A14 (ATB0,+) and SLC7A5 (LAT1), that are known to be essential for the sustenance of amino acid metabolism in most cancers. The LJ@Trp-NPs uses tryptophan to guide SLC6A14-targeted delivery of JPH203, a high-affinity inhibitor of SLC7A5. In the process, SLC6A14 is also down-regulated. We tested the ability of this strategy to synergize with the anticancer efficacy of lapatinib, an inhibitor of EGFR/HER1/HER2-assocated kinase. These studies show that blockade of amino acid entry amplifies the anticancer effect of lapatinib via interference with mTOR signaling, promotion of apoptosis, and suppression of cell proliferation and metastasis. This represents the first study to evaluate the impact of amino acid starvation on the anticancer efficacy of widely used kinase inhibitor.
    Keywords:  ATB0,+ targeting; Amino acid delivery; Cancer therapy; Nanoparticles; mTOR
    DOI:  https://doi.org/10.1016/j.bioactmat.2021.07.009
  8. Cancer Lett. 2021 Nov 20. pii: S0304-3835(21)00591-7. [Epub ahead of print]
    Succinate receptor 1 inhibits mitochondrial respiration in cancer cells addicted to glutamine.
    Philipp Rabe, Aenne-Dorothea Liebing, Petra Krumbholz, Robert Kraft, Claudia Stäubert.
      Cancer cells display metabolic alterations to meet the bioenergetic demands for their high proliferation rates. Succinate is a central metabolite of the tricarboxylic acid (TCA) cycle, but was also shown to act as an oncometabolite and to specifically activate the succinate receptor 1 (SUCNR1), which is expressed in several types of cancer. However, functional studies focusing on the connection between SUCNR1 and cancer cell metabolism are still lacking. In the present study, we analyzed the role of SUCNR1 for cancer cell metabolism and survival applying different signal transduction, metabolic and imaging analyses. We chose a gastric, a lung and a pancreatic cancer cell line for which our data revealed functional expression of SUCNR1. Further, presence of glutamine (Gln) caused high respiratory rates and elevated expression of SUCNR1. Knockdown of SUCNR1 resulted in a significant increase of mitochondrial respiration and superoxide production accompanied by an increase in TCA cycle throughput and a reduction of cancer cell survival in the analyzed cancer cell lines. Combination of SUCNR1 knockdown and treatment with the chemotherapeutics cisplatin and gemcitabine further increased cancer cell death. In summary, our data implicates that SUCNR1 is crucial for Gln-addicted cancer cells by limiting TCA cycle throughput, mitochondrial respiration and the production of reactive oxygen species, highlighting its potential as a pharmacological target for cancer treatment.
    Keywords:  Cancer metabolism; GPR91; Glutaminolysis; Metabolite-sensing GPCR; SUCNR1
    DOI:  https://doi.org/10.1016/j.canlet.2021.11.024
  9. Expert Opin Ther Targets. 2021 Nov 25.
    The mechanisms and therapeutic targets of ferroptosis in cancer.
    Long Ye, Fengyan Jin, Shaji K Kumar, Yun Dai.
       INTRODUCTION: Ferroptosis, a form of programmed cell death, is mediated primarily by lipid peroxidation via a unique iron-dependent process. The mechanisms of ferroptosis involve the metabolisms of amino acids, irons, and lipids, and the regulation of antioxidant systems. Evidence supports the roles of ferroptosis in cancer, while metabolic reprogramming (a hallmark of cancer) renders tumor cells highly vulnerable to ferroptosis and thus provides a rationale for ferroptosis-targeted therapy for cancer.
    AREA COVERED: This article examines the current understanding of the mechanisms and related signaling pathways involving ferroptosis; it focuses on novel targets in cancer and its treatment and drug resistance. The development of ferroptosis-targeted therapy, especially in combination with conventional or non-conventional therapies, are considered with dilemmas and key questions in this research area.
    EXPERT OPINION: An increasing number of potential targets and ferroptosis inducers (FINs) have been identified to treat cancer. However, no specific FIN has entered clinical trials thus far, likely due to poor efficacy and high toxicity in vivo. Thus, new FINs with high selectivity and bioavailability are required to target tumor cells more specifically and potently. Particularly, the combination of FINs with chemotherapy, radiotherapy, targeted therapy, and immunotherapy warrants clinical investigation in the future.
    Keywords:  altretamine; auranofin; cancer; cisplatin; combination therapy; drug resistance; ferroptosis; fubendazole; itraconazole; ivosidenib; lapatinib; metabolic reprogramming; methotrexat; mitochondrial dysregulation; pioglitazone; programmed cell death; rosiglitazone; sorafenib; statins; sulfasalazine; therapeutic target; troglitazone; zileuton
    DOI:  https://doi.org/10.1080/14728222.2021.2011206
  10. Pharmaceutics. 2021 Oct 25. pii: 1785. [Epub ahead of print]13(11):
    Nanoparticles for Ferroptosis Therapy in Cancer.
    Nadia Zaffaroni, Giovanni Luca Beretta.
      Ferroptosis is a regulated cell death mechanism holding promise for anticancer therapy. Numerous small molecules inducing ferroptosis have been reported thus far. However, these compounds suffer from important drawbacks including poor solubility, systemic toxicity, and scarce tumor targeting ability that have limited their clinical success. The notion that nanoparticles inducing ferroptosis show better preclinical profiles compared to small molecules and overcome resistance to apoptosis has opened a new scenario for cancer treatment. Due to peculiar chemical-physical properties, nanoparticles can be loaded with anticancer drugs or decorated with tumor-selecting molecules. These features allow for drug combination treatment as well as tumor targeting. In the review, we summarize and discuss the available information concerning nanoparticles inducing ferroptosis endowed with different peculiarities and suitable for therapeutic purposes including nanoparticles for (i) antitumor drug delivery, (ii) tumor targeting, (iii) immunomodulation, and (iv) radiofrequency ablation, hyperthermia, and photodynamic therapy.
    Keywords:  cancer; ferroptosis; iron; nanoparticles; tumor targeting
    DOI:  https://doi.org/10.3390/pharmaceutics13111785
  11. PLoS One. 2021 ;16(11): e0260400
    Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
    Pritpal Kaur, Shreya Nagar, Madhura Bhagwat, Mohammad Uddin, Yan Zhu, Ivana Vancurova, Ales Vancura.
      Heme is an essential cofactor for enzymes of the electron transport chain (ETC) and ATP synthesis in mitochondrial oxidative phosphorylation (OXPHOS). Heme also binds to and destabilizes Bach1, a transcription regulator that controls expression of several groups of genes important for glycolysis, ETC, and metastasis of cancer cells. Heme synthesis can thus affect pathways through which cells generate energy and precursors for anabolism. In addition, increased heme synthesis may trigger oxidative stress. Since many cancers are characterized by a high glycolytic rate regardless of oxygen availability, targeting glycolysis, ETC, and OXPHOS have emerged as a potential therapeutic strategy. Here, we report that enhancing heme synthesis through exogenous supplementation of heme precursor 5-aminolevulinic acid (ALA) suppresses oxidative metabolism as well as glycolysis and significantly reduces proliferation of both ovarian and breast cancer cells. ALA supplementation also destabilizes Bach1 and inhibits migration of both cell types. Our data indicate that the underlying mechanisms differ in ovarian and breast cancer cells, but involve destabilization of Bach1, AMPK activation, and induction of oxidative stress. In addition, there appears to be an inverse correlation between the activity of oxidative metabolism and ALA sensitivity. Promoting heme synthesis by ALA supplementation may thus represent a promising new anti-cancer strategy, particularly in cancers that are sensitive to altered redox signaling, or in combination with strategies that target the antioxidant systems or metabolic weaknesses of cancer cells.
    DOI:  https://doi.org/10.1371/journal.pone.0260400
  12. Pharmaceutics. 2021 Nov 04. pii: 1867. [Epub ahead of print]13(11):
    Metallic Nanoparticle-Mediated Immune Cell Regulation and Advanced Cancer Immunotherapy.
    Adityanarayan Mohapatra, Padmanaban Sathiyamoorthy, In-Kyu Park.
      Cancer immunotherapy strategies leveraging the body's own immune system against cancer cells have gained significant attention due to their remarkable therapeutic efficacy. Several immune therapies have been approved for clinical use while expanding the modalities of cancer therapy. However, they are still not effective in a broad range of cancer patients because of the typical immunosuppressive microenvironment and limited antitumor immunity achieved with the current treatment. Novel approaches, such as nanoparticle-mediated cancer immunotherapies, are being developed to overcome these challenges. Various types of nanoparticles, including liposomal, polymeric, and metallic nanoparticles, are reported for the development of effective cancer therapeutics. Metallic nanoparticles (MNPs) are one of the promising candidates for anticancer therapy due to their unique theranostic properties and are thus explored as both imaging and therapeutic agents. In addition, MNPs offer a dense surface functionalization to target tumor tissue and deliver genetic, therapeutic, and immunomodulatory agents. Furthermore, MNPs interact with the tumor microenvironment (TME) and regulate the levels of tumor hypoxia, glutathione (GSH), and reactive oxygen species (ROS) for remodulation of TME for successful therapy. In this review, we discuss the role of nanoparticles in tumor microenvironment modulation and anticancer therapy. In particular, we evaluated the response of MNP-mediated immune cells, such as dendritic cells, macrophages, T cells and NK cells, against tumor cells and analyzed the role of MNP-based cancer therapies in regulating the immunosuppressive environment.
    Keywords:  antitumor immune response; cancer immunotherapy; immune cell regulation; metallic nanoparticle; tumor microenvironment modulation
    DOI:  https://doi.org/10.3390/pharmaceutics13111867
  13. Cells. 2021 Nov 02. pii: 2981. [Epub ahead of print]10(11):
    Ferroptosis: Cancer Stem Cells Rely on Iron until "to Die for" It.
    Emma Cosialls, Rima El Hage, Leïla Dos Santos, Chang Gong, Maryam Mehrpour, Ahmed Hamaï.
      Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells with stem cell-like features. Able to initiate and sustain tumor growth and mostly resistant to anti-cancer therapies, they are thought responsible for tumor recurrence and metastasis. Recent accumulated evidence supports that iron metabolism with the recent discovery of ferroptosis constitutes a promising new lead in the field of anti-CSC therapeutic strategies. Indeed, iron uptake, efflux, storage and regulation pathways are all over-engaged in the tumor microenvironment suggesting that the reprogramming of iron metabolism is a crucial occurrence in tumor cell survival. In particular, recent studies have highlighted the importance of iron metabolism in the maintenance of CSCs. Furthermore, the high concentration of iron found in CSCs, as compared to non-CSCs, underlines their iron addiction. In line with this, if iron is an essential macronutrient that is nevertheless highly reactive, it represents their Achilles' heel by inducing ferroptosis cell death and therefore providing opportunities to target CSCs. In this review, we first summarize our current understanding of iron metabolism and its regulation in CSCs. Then, we provide an overview of the current knowledge of ferroptosis and discuss the role of autophagy in the (regulation of) ferroptotic pathways. Finally, we discuss the potential therapeutic strategies that could be used for inducing ferroptosis in CSCs to treat cancer.
    Keywords:  autophagy; cancer stem cells; ferroptosis; iron metabolism
    DOI:  https://doi.org/10.3390/cells10112981
  14. Cancers (Basel). 2021 Nov 09. pii: 5599. [Epub ahead of print]13(22):
    Oncogenic KRAS: Signaling and Drug Resistance.
    Hyeon Jin Kim, Han Na Lee, Mi Suk Jeong, Se Bok Jang.
      RAS proteins play a role in many physiological signals transduction processes, including cell growth, division, and survival. The Ras protein has amino acids 188-189 and functions as GTPase. These proteins are switch molecules that cycle between inactive GDP-bound and active GTP-bound by guanine nucleotide exchange factors (GEFs). KRAS is one of the Ras superfamily isoforms (N-RAS, H-RAS, and K-RAS) that frequently mutate in cancer. The mutation of KRAS is essentially performing the transformation in humans. Since most RAS proteins belong to GTPase, mutated and GTP-bound active RAS is found in many cancers. Despite KRAS being an important molecule in mostly human cancer, including pancreatic and breast, numerous efforts in years past have persisted in cancer therapy targeting KRAS mutant. This review summarizes the biological characteristics of these proteins and the recent progress in the exploration of KRAS-targeted anticancer, leading to new insight.
    Keywords:  GTPase; KRAS; drug resistance; inhibitor; mutant; signaling
    DOI:  https://doi.org/10.3390/cancers13225599
  15. Int J Mol Sci. 2021 Nov 18. pii: 12455. [Epub ahead of print]22(22):
    Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach.
    Torki A Zughaibi, Mohd Suhail, Mohammad Tarique, Shams Tabrez.
      Cancer is, globally, one of the main causes of death. Even though various therapies are available, they are still painful because of their adverse side effects. Available treatments frequently fail due to unpromising responses, resistance to classical anticancer drugs, radiation therapy, chemotherapy, and low accessibility to tumor tissues. Developing novel strategies to minimize adverse side effects, improve chemotherapy sensitivity, and control cancer progression is needed. Many studies have suggested small dietary molecules as complementary treatments for cancer patients. Different components of herbal/edible plants, known as flavonoids, have recently garnered attention due to their broad biological properties (e.g., antioxidant, antiviral, antimicrobial, anti-inflammatory, anti-mutagenic, anticancer, hepatoprotective, and cardioprotective). These flavonoids have shown anticancer activity by affecting different signaling cascades. This article summarizes the key progress made in this area and discusses the role of flavonoids by specifically inhibiting the PI3K/Akt/mTOR pathway in various cancers.
    Keywords:  Akt; PI3K; cancer; flavonoids; inhibitors; mTOR
    DOI:  https://doi.org/10.3390/ijms222212455
  16. Cancers (Basel). 2021 Nov 10. pii: 5622. [Epub ahead of print]13(22):
    Understanding the Role of Autophagy in Cancer Formation and Progression Is a Real Opportunity to Treat and Cure Human Cancers.
    Simone Patergnani, Sonia Missiroli, Giampaolo Morciano, Mariasole Perrone, Cristina M Mantovani, Gabriele Anania, Francesco Fiorica, Paolo Pinton, Carlotta Giorgi.
      The malignant transformation of a cell produces the accumulation of several cellular adaptions. These changes determine variations in biological processes that are necessary for a cancerous cell to survive during stressful conditions. Autophagy is the main nutrient recycling and metabolic adaptor mechanism in eukaryotic cells, represents a continuous source of energy and biomolecules, and is fundamental to preserve the correct cellular homeostasis during unfavorable conditions. In recent decades, several findings demonstrate a close relationship between autophagy, malignant transformation, and cancer progression. The evidence suggests that autophagy in the cancer context has a bipolar role (it may act as a tumor suppressor and as a mechanism of cell survival for established tumors) and demonstrates that the targeting of autophagy may represent novel therapeutic opportunities. Accordingly, the modulation of autophagy has important clinical benefits in patients affected by diverse cancer types. Currently, about 30 clinical trials are actively investigating the efficacy of autophagy modulators to enhance the efficacy of cytotoxic chemotherapy treatments. A deeper understanding of the molecular pathways regulating autophagy in the cancer context will provide new ways to target autophagy for improving the therapeutic benefits. Herein, we describe how autophagy participates during malignant transformation and cancer progression, and we report the ultimate efforts to translate this knowledge into specific therapeutic approaches to treat and cure human cancers.
    Keywords:  autophagy; cancer; clinical trials; therapy; tumor suppression
    DOI:  https://doi.org/10.3390/cancers13225622
  17. Theranostics. 2021 ;11(20): 9937-9952
    Targeting ferroptosis-based cancer therapy using nanomaterials: strategies and applications.
    Lianxiang Luo, Han Wang, Wen Tian, Xiaoling Li, Zheng Zhu, Riming Huang, Hui Luo.
      As an iron-dependent mode of programmed cell death induced by lipid peroxidation, ferroptosis plays an important role in cancer therapy. The metabolic reprogramming in tumor microenvironment allows the possibility of targeting ferroptosis in cancer treatment. Recent studies reveal that nanomaterials targeting ferroptosis have prospects for the development of new cancer treatments. However, the design ideas of nanomaterials targeting ferroptosis sometimes vary. Therefore, in addition to the need for a systematic summary of these ideas, new ideas and insights are needed to make possible the construction of nanomaterials for effectively targeting this cell death pathway. At the same time, further optimization of nanomaterials design is required to make them appropriate for clinical treatment. In this context, we summarize this cross-cutting research area covering from the known mechanism of ferroptosis to providing feasible ideas for nanomaterials design as well as their clinical application. We aim to provide new insights and enlightenment for the next step in developing new nanomaterials for cancer treatment.
    Keywords:  Cancer therapy; Clinical strategy; Ferroptosis; Nanomaterials; Tumor microenvironment
    DOI:  https://doi.org/10.7150/thno.65480
  18. Biomedicines. 2021 Oct 22. pii: 1522. [Epub ahead of print]9(11):
    Immunomodulatory Effects of a Concoction of Natural Bioactive Compounds-Mechanistic Insights.
    Vani Gangwar, Amar Garg, Karan Lomore, Kalyani Korla, Shruthi S Bhat, Raghavendra P Rao, Mohamed Rafiq, Rajesh Kumawath, Babu V Uddagiri, Venkatesh V Kareenhalli.
      Natural bioactive compounds derived from plant-based products are known for their biological immunomodulatory activities. They possess systemic pleiotropic effects, minimal side effects, and very low toxicities. Plant-based bioactive compounds have tremendous potential as natural therapeutic entities against various disease conditions and act as anti-inflammatory, antioxidant, anti-mutagenic, anti-microbial, anti-viral, anti-tumour, anti-allergic, neuroprotective, and cardioprotective agents. A herbal formulation extract including five biologically active compounds: Apigenin, Quercetin, Betulinic acid, Oleanolic acid, and β-Sitosterol can impart several immunomodulatory effects. In this review, we systematically present the impact of these compounds on important molecular signaling pathways, including inflammation, immunity, redox metabolism, neuroinflammation, neutropenia, cell growth, apoptosis, and cell cycle. The review corroborates the beneficial effect of these compounds and shows considerable potential to be used as a safer, more cost-effective treatment for several diseases by affecting the major nodal points of various stimulatory pathways.
    Keywords:  Apigenin; Betulinic acid; Oleanolic acid; Quercetin; autoimmune diseases; cancer; inflammation; neutropenia; oxidative stress; β-Sitosterol
    DOI:  https://doi.org/10.3390/biomedicines9111522
  19. Pharmaceuticals (Basel). 2021 Oct 22. pii: 1068. [Epub ahead of print]14(11):
    New Insights into Curcumin- and Resveratrol-Mediated Anti-Cancer Effects.
    Andrea Arena, Maria Anele Romeo, Rossella Benedetti, Laura Masuelli, Roberto Bei, Maria Saveria Gilardini Montani, Mara Cirone.
      Curcumin and resveratrol are bioactive natural compounds displaying anti-inflammatory, anti-oxidant and anti-cancer properties. In this study, we compared the cytotoxic effects of these molecules and the molecular mechanisms involved against Her-2/neu-positive breast and salivary cancer cell lines. We found that both curcumin and resveratrol were efficient in reducing cancer cell survival and that they differently affected autophagy, ROS and activation of the PI3K/AKT/mTOR pathway. Moreover, we found that resveratrol and curcumin in combination exerted a stronger cytotoxic effect in correlation with the induction of a stronger ER stress and the upregulation of pro-death UPR molecule CHOP. This effect also correlated with the induction of pro-survival autophagy by curcumin and its inhibition by resveratrol. In conclusion, this study unveils new molecular mechanisms underlying the anti-cancer effects of resveratrol, curcumin and their combination, which can help to design new therapeutic strategies based on the use of these polyphenols.
    Keywords:  ER stress; Her-2/neu cancers; PI3K/AKT/mTOR; autophagy; curcumin; resveratrol
    DOI:  https://doi.org/10.3390/ph14111068
  20. Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01519-9. [Epub ahead of print]37(8): 110037
    Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets.
    Accalia Fu, Lara van Rooyen, Lindsay Evans, Nina Armstrong, Daina Avizonis, Tatsuya Kin, Gregory H Bird, Anita Reddy, Edward T Chouchani, Marc Liesa-Roig, Loren D Walensky, A M James Shapiro, Nika N Danial.
      Glucose metabolism modulates the islet β cell responses to diabetogenic stress, including inflammation. Here, we probed the metabolic mechanisms that underlie the protective effect of glucose in inflammation by interrogating the metabolite profiles of primary islets from human donors and identified de novo glutathione synthesis as a prominent glucose-driven pro-survival pathway. We find that pyruvate carboxylase is required for glutathione synthesis in islets and promotes their antioxidant capacity to counter inflammation and nitrosative stress. Loss- and gain-of-function studies indicate that pyruvate carboxylase is necessary and sufficient to mediate the metabolic input from glucose into glutathione synthesis and the oxidative stress response. Altered redox metabolism and cellular capacity to replenish glutathione pools are relevant in multiple pathologies beyond obesity and diabetes. Our findings reveal a direct interplay between glucose metabolism and glutathione biosynthesis via pyruvate carboxylase. This metabolic axis may also have implications in other settings where sustaining glutathione is essential.
    Keywords:  ROS; glucose; glutathione; inflammation; nitrosative stress; oxidative stress; pancreatic islets; pyruvate carboxylase
    DOI:  https://doi.org/10.1016/j.celrep.2021.110037
  21. Ann Transl Med. 2021 Oct;9(19): 1503
    Mechanisms and pharmacological applications of ferroptosis: a narrative review.
    Jing-Jing Zhang, Jing Du, Ni Kong, Guang-Yu Zhang, Meng-Zhen Liu, Chong Liu.
       Objective: We aimed at comprehensively analyzing ferroptosis regulation and its potential role in the treatment of associated diseases.
    Background: Ferroptosis is a recently discovered form of cell death that involves small molecule-induced oxidative cell death. This process is usually accompanied by large amounts of iron accumulation and lipid peroxidation. Ferroptosis inducers directly or indirectly affect glutathione peroxidase (GPXs) through different pathways. Disturbances in GPXs result in suppressed cellular antioxidant capacities, accumulation of lipid reactive oxygen species (ROS) and oxidative cell death. It has been reported that ferroptosis is closely associated with the pathophysiological processes of many diseases, including tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury and iron metabolism diseases among others.
    Methods: First, we reviewed the mechanisms of ferroptosis, with emphasis on the characteristics and functions of ferroptosis in multiple pathways. Then, inducers and inhibitors of ferroptosis were reviewed, and their mechanisms of action elucidated. Finally, ferroptosis-associated pathophysiological processes of various diseases were reviewed.
    Conclusions: Ferroptosis is associated with the occurrence and development of various diseases. Elucidation of the mechanisms involved in ferroptosis will inform new therapeutic targets and strategies for these diseases.
    Keywords:  Ferroptosis; glutathione peroxidase; iron accumulation; lipid peroxidation
    DOI:  https://doi.org/10.21037/atm-21-1595
  22. Pharmaceutics. 2021 Nov 01. pii: 1829. [Epub ahead of print]13(11):
    Targeting Engineered Nanoparticles for Breast Cancer Therapy.
    Kumar Ganesan, Yan Wang, Fei Gao, Qingqing Liu, Chen Zhang, Peng Li, Jinming Zhang, Jianping Chen.
      Breast cancer (BC) is the second most common cancer in women globally after lung cancer. Presently, the most important approach for BC treatment consists of surgery, followed by radiotherapy and chemotherapy. The latter therapeutic methods are often unsuccessful in the treatment of BC because of their various side effects and the damage incurred to healthy tissues and organs. Currently, numerous nanoparticles (NPs) have been identified and synthesized to selectively target BC cells without causing any impairments to the adjacent normal tissues or organs. Based on an exploratory study, this comprehensive review aims to provide information on engineered NPs and their payloads as promising tools in the treatment of BC. Therapeutic drugs or natural bioactive compounds generally incorporate engineered NPs of ideal sizes and shapes to enhance their solubility, circulatory half-life, and biodistribution, while reducing their side effects and immunogenicity. Furthermore, ligands such as peptides, antibodies, and nucleic acids on the surface of NPs precisely target BC cells. Studies on the synthesis of engineered NPs and their impact on BC were obtained from PubMed, Science Direct, and Google Scholar. This review provides insights on the importance of engineered NPs and their methodology for validation as a next-generation platform with preventive and therapeutic effects against BC.
    Keywords:  breast cancer; engineering; ligands; nanoparticles; therapeutic effects
    DOI:  https://doi.org/10.3390/pharmaceutics13111829
  23. Mol Nutr Food Res. 2021 Nov 21. e2100732
    Targeting AMPK Signaling by Dietary Polyphenols in Cancer Prevention.
    Zuomin Hu, Mengyuan Li, Yunyun Cao, Otobong Donald Akan, Tianyi Guo, Feijun Luo.
      Cancer is a serious public health problem in the world and a major disease affecting human health. Dietary polyphenols have shown good potential in the treatment of various cancers. It is worth noting that cancer cells usually exhibit metabolic abnormalities of high glucose intake and inefficient utilization. AMPK is the key molecule in the regulation of energy metabolism and is closely related with obesity and diabetes. Recent studies indicate that AMPK also plays an important role in cancer prevention and regulating cancer-related genes and pathways, and dietary polyphenols can significantly regulate AMPK activity. In this review, we systemically summarized the progress of dietary polyphenols preventing carcinogenesis via AMPK pathway. From the view point of interfering energy metabolism, the anti-cancer effects of dietary polyphenols were explained. AMPK pathway modulated by different dietary polyphenols affects pathways and target genes were summarized. Dietary polyphenols exert anti-cancer effect through the target molecules regulated by AMPK, which broadens our understanding of polyphenols anti-cancer mechanisms and provides value reference for the investigators of the novel field. This article is protected by copyright. All rights reserved.
    Keywords:  AMPK; cancer; dietary polyphenols; energy metabolism; molecular mechanism
    DOI:  https://doi.org/10.1002/mnfr.202100732
  24. Antioxidants (Basel). 2021 Oct 28. pii: 1718. [Epub ahead of print]10(11):
    Resveratrol Targets a Variety of Oncogenic and Oncosuppressive Signaling for Ovarian Cancer Prevention and Treatment.
    Xue-Ling Xu, Shou-Long Deng, Zheng-Xing Lian, Kun Yu.
      Ovarian cancer is a heterogeneous disease and is also the major cause of death among women from gynecologic malignancies. A combination of surgery and chemotherapy is the major therapy for ovarian cancer. Unfortunately, despite good response rates to initial surgery and chemotherapy, most patients relapse and have a generally poor survival rate. The present research sheds light on the therapeutic effects of multiple natural products in patients with ovarian cancer. Notably, these natural ingredients do not have adverse effects on healthy cells and tissues, indicating that natural products can serve as a safe alternative therapy for ovarian cancer. Trans-3,4,5'-Trihydroxystibene (resveratrol) is a natural product that is commonly found in the human diet and that has been shown to have anticancer effects on various human cancer cells. This review summarizes current knowledge regarding the progress of resveratrol against tumor cell proliferation, metastasis, apoptosis induction, autophagy, sensitization, and antioxidation as well as anti-inflammation. It also provides information regarding the role of resveratrol analogues in ovarian cancer. A better understanding of the role of resveratrol in ovarian cancer may provide a new array for the prevention and therapy of ovarian cancer.
    Keywords:  antioxidant; antitumor; ovarian cancer; resveratrol
    DOI:  https://doi.org/10.3390/antiox10111718
  25. J Mammary Gland Biol Neoplasia. 2021 Nov 23.
    Chloroquine Induces ROS-mediated Macrophage Migration Inhibitory Factor Secretion and Epithelial to Mesenchymal Transition in ER-positive Breast Cancer Cell Lines.
    Guadalupe Rojas-Sanchez, Alin García-Miranda, José Benito Montes-Alvarado, Israel Cotzomi-Ortega, Fabiola Lilí Sarmiento-Salinas, Eduardo Eleazar Jimenez-Ignacio, Dalia Ramírez-Ramírez, Rubí Esmeralda Romo-Rodríguez, Julio Reyes-Leyva, Verónica Vallejo-Ruiz, Nidia Gary Pazos-Salazar, Paola Maycotte.
      Breast cancer (BC) is the leading cause of cancer-related death in women in the world. Since tumor cells employ autophagy as a survival pathway, it has been proposed that autophagy inhibition could be beneficial for cancer treatment. There are several onging clinical trials where autophagy is being inhibited (using chloroquine, CQ or hydroxychloroquine, HCQ) along with chemotherapy with promising results. However, there is also in vitro evidence in which autophagy inhibition can induce epithelial to mesenchymal transition (EMT) in cancer cells, indicating that, at least in some cases, this strategy could be detrimental for cancer patients. In this study, we found that the genetic inhibition of autophagy primed cells for EMT by inducing a decrease in E-cadherin protein levels, while CQ treatment decreased E-cadherin levels, induced morphological changes related to EMT, increased EMT-related transcription factor (EMT-TF) expression and migration in estrogen receptor positive (ER +) BC cell lines. Importantly, CQ treatment increased intracellular reactive oxygen species (ROS) which induced the secretion of macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine related to malignancy. Both ROS production and MIF secretion were responsible for the mesenchymal morphology and increased migratory capacity induced by CQ. Our results indicate that CQ treatment increased malignancy by inducing ROS production, MIF secretion and EMT and suggest that autophagy inhibition in ER + BC patients might have detrimental effects. Our data indicates that a careful selection of patients should be performed in order to determine who will benefit the most from autophagy inhibition with available pharmacological agents for the treatment of breast cancer.
    Keywords:  Autophagy; Breast cancer; Chloroquine; Epithelial-mesenchymal transition; Macrophage migration inhibitory factor
    DOI:  https://doi.org/10.1007/s10911-021-09503-5
  26. Cancers (Basel). 2021 Nov 17. pii: 5753. [Epub ahead of print]13(22):
    Phytochemicals as an Alternative or Integrative Option, in Conjunction with Conventional Treatments for Hepatocellular Carcinoma.
    Sheryl Rodriguez, Kristy Skeet, Tugba Mehmetoglu-Gurbuz, Madeline Goldfarb, Shri Karri, Jackelyn Rocha, Mark Shahinian, Abdallah Yazadi, Seeta Poudel, Ramadevi Subramani.
      Hepatocellular carcinoma (HCC) is the most abundant form of liver cancer. It accounts for 75-85% of liver cancer cases and, though it ranks globally as the sixth most common cancer, it ranks second in cancer-related mortality. Deaths from HCC are usually due to metastatic spread of the cancer. Unfortunately, there are many challenges and limitations with the latest HCC therapies and medications, making it difficult for patients to receive life-prolonging care. As there is clearly a high demand for alternative therapy options for HCC, it is prudent to turn to plants for the solution, as their phytochemicals have long been used and revered for their many medicinal purposes. This review explores the promising phytochemical compounds identified from pre-clinical and clinical trials being used either independently or in conjunction with already existing cancer therapy treatments. The phytochemicals discussed in this review were classified into several categories: lipids, polyphenols, alkaloids, polysaccharides, whole extracts, and phytochemical combinations. Almost 80% of the compounds failed to progress into clinical studies due to lack of information regarding the toxicity to normal cells and bioavailability. Although large obstacles remain, phytochemicals can be used either as an alternative or integrative therapy in conjunction with existing HCC chemotherapies. In conclusion, phytochemicals have great potential as treatment options for hepatocellular carcinoma.
    Keywords:  hepatocellular carcinoma; liver cancer; metastasis; natural compounds; phytochemicals
    DOI:  https://doi.org/10.3390/cancers13225753
  27. Nanomaterials (Basel). 2021 Nov 20. pii: 3132. [Epub ahead of print]11(11):
    Nanoparticle Systems for Cancer Phototherapy: An Overview.
    Thais P Pivetta, Caroline E A Botteon, Paulo A Ribeiro, Priscyla D Marcato, Maria Raposo.
      Photodynamic therapy (PDT) and photothermal therapy (PTT) are photo-mediated treatments with different mechanisms of action that can be addressed for cancer treatment. Both phototherapies are highly successful and barely or non-invasive types of treatment that have gained attention in the past few years. The death of cancer cells because of the application of these therapies is caused by the formation of reactive oxygen species, that leads to oxidative stress for the case of photodynamic therapy and the generation of heat for the case of photothermal therapies. The advancement of nanotechnology allowed significant benefit to these therapies using nanoparticles, allowing both tuning of the process and an increase of effectiveness. The encapsulation of drugs, development of the most different organic and inorganic nanoparticles as well as the possibility of surfaces' functionalization are some strategies used to combine phototherapy and nanotechnology, with the aim of an effective treatment with minimal side effects. This article presents an overview on the use of nanostructures in association with phototherapy, in the view of cancer treatment.
    Keywords:  cancer; nanoparticles; photodynamic therapy; phototherapy; photothermal therapy
    DOI:  https://doi.org/10.3390/nano11113132
  28. Cells. 2021 Oct 29. pii: 2944. [Epub ahead of print]10(11):
    Mechanisms, Diagnosis and Treatment of Bone Metastases.
    Jozef Ban, Valerie Fock, Dave N T Aryee, Heinrich Kovar.
      Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients' quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.
    Keywords:  EMT; bone colonization; bone metastasis; bone reconstruction; metastasis targeted therapy; metastatic dormancy; metastatic niche; tumor microenvironment interactions
    DOI:  https://doi.org/10.3390/cells10112944
  29. Int J Biochem Cell Biol. 2021 Nov 23. pii: S1357-2725(21)00204-1. [Epub ahead of print] 106123
    HuaChanSu suppresses tumor growth and interferes with glucose metabolism in hepatocellular carcinoma cells by restraining Hexokinase-2.
    Qi Wu, Shao-Ping Wang, Xiao-Xue Sun, Yu-Fan Tao, Xiao-Qing Yuan, Qi-Mei Chen, Long Dai, Chun-Lei Li, Jia-Yu Zhang, Ai-Lin Yang.
      Hepatocellular carcinoma (HCC) has become the sixth highly diagnosed cancer and the fourth main reason of cancer deaths worldwide. HuaChanSu, an extract from dried toad skin, exhibits good anticancer effects and has been widely used in the treatment of liver cancer. The reprogramming of glucose metabolism is one remarkable feature of hepatocellular carcinoma, and the effects of HuaChanSu on the abnormal glucose metabolism of cancer cells have not been elucidated. In our study, we investigate the effects of HuaChanSu on glucose metabolism of hepatocellular carcinoma cells and tumor growth in vivo. The results show that HuaChanSu inhibits the tumor growth of hepatoma H22-bearing mice and prolongs the survival time of tumor-bearing mice, additionally, HuaChanSu has no obvious adverse effects in these mice. In vitro, HuaChanSu restrains the proliferation, induces apoptosis and cell cycle arrest of human hepatoma cells. HuaChanSu also promotes ROS production and causes mitochondrial damage. Furthermore, HuaChanSu inhibits glucose uptake and lactate release in human hepatoma cells. Mechanistically, we find that HuaChanSu downregulates Hexokinase-2 (HK2) expression, and using RNA interference, we confirm that HuaChanSu suppresses the growth of HepG2 cells by interfering with glucose metabolism through downregulation of Hexokinase-2. However, knockdown of Hexokinase-2 has no obvious effect on the proliferation of SK-HEP-1 cells, although glucose uptake and lactate release are reduced in siHK2-transfected SK-HEP-1 cells, subsequently, we illustrate that two human hepatoma cell lines exhibit glucose metabolism heterogeneity, which causes the different cell proliferation responses to the inhibition of Hexokinase-2. Taken together, our study indicates that HuaChanSu could inhibit tumor growth and interfere with glucose metabolism via suppression of Hexokinase-2, and these findings provide a new insight into the anti-hepatoma mechanisms of HuaChanSu and lay a theoretical foundation for the further clinical application of HuaChanSu.
    Keywords:  HuaChanSu; glucose metabolism; hepatocellular carcinoma; hexokinase-2
    DOI:  https://doi.org/10.1016/j.biocel.2021.106123
  30. Acta Pharmacol Sin. 2021 Nov 22.
    The double faced role of xanthine oxidoreductase in cancer.
    Man-Man Chen, Ling-Hua Meng.
      Xanthine oxidoreductase (XOR) is a critical, rate-limiting enzyme that controls the last two steps of purine catabolism by converting hypoxanthine to xanthine and xanthine to uric acid. It also produces reactive oxygen species (ROS) during the catalytic process. The enzyme is generally recognized as a drug target for the therapy of gout and hyperuricemia. The catalytic products uric acid and ROS act as antioxidants or oxidants, respectively, and are involved in pro/anti-inflammatory actions, which are associated with various disease manifestations, including metabolic syndrome, ischemia reperfusion injury, cardiovascular disorders, and cancer. Recently, extensive efforts have been devoted to understanding the paradoxical roles of XOR in tumor promotion. Here, we summarize the expression of XOR in different types of cancer and decipher the dual roles of XOR in cancer by its enzymatic or nonenzymatic activity to provide an updated understanding of the mechanistic function of XOR in cancer. We also discuss the potential to modulate XOR in cancer therapy.
    Keywords:  ROS; cancer therapy; uric acid; xanthine oxidoreductase (XOR)
    DOI:  https://doi.org/10.1038/s41401-021-00800-7
  31. Front Genet. 2021 ;12 768996
    Metabolic Fuel for Epigenetic: Nuclear Production Meets Local Consumption.
    Ruben Boon.
      Epigenetic modifications are responsible for finetuning gene expression profiles to the needs of cells, tissues, and organisms. To rapidly respond to environmental changes, the activity of chromatin modifiers critically depends on the concentration of a handful of metabolites that act as substrates and co-factors. In this way, these enzymes act as metabolic sensors that directly link gene expression to metabolic states. Although metabolites can easily diffuse through the nuclear pore, molecular mechanisms must be in place to regulate epigenetic marker deposition in specific nuclear subdomains or even on single loci. In this review, I explore the possible subcellular sites of metabolite production that influence the epigenome. From the relationship between cytoplasmic metabolism and nuclear metabolite deposition, I converse to the description of a compartmentalized nuclear metabolism. Last, I elaborate on the possibility of metabolic enzymes to operate in phase-separated nuclear microdomains formed by multienzyme and chromatin-bound protein complexes.
    Keywords:  chromatin; compartmentalization; epigenetics; liquid-liquid phase separation (LLPS); nuclear metabolism
    DOI:  https://doi.org/10.3389/fgene.2021.768996
  32. Front Oncol. 2021 ;11 758884
    Current Strategies for Cancer Cell-Derived Extracellular Vesicles for Cancer Therapy.
    Weijian Lin, Xing-Dong Cai.
      Cancer cell-derived extracellular vesicles (CEVs), a novel type of therapeutic agent in cancer treatment, can be prepared from the autocrine secretion of various cancer cells, the direct extraction of cancer cells and the combination of cancer cell-derived membranes with advanced materials. With various bioactive molecules, exosomes are produced by cells for intercellular communication. Although cancer cell-derived exosomes are known to inhibit tumor apoptosis and promote the progression of cancer, researchers have developed various innovative strategies to prepare anti-tumor vesicles from cancer cells. With current strategies for anti-tumor vesicles, four different kinds of CEVs are classified including irradiated CEVs, advanced materials combined CEVs, chemotherapeutic drugs loaded CEVs and genetically engineered CEVs. In this way, CEVs can not only be the carriers for anti-tumor drugs to the target tumor area but also act as immune-active agents. Problems raised in the strategies mainly concerned with the preparation, efficacy and application. In this review, we classified and summarized the current strategies for utilizing the anti-tumor potential of CEVs. Additionally, the challenges and the prospects of this novel agent have been discussed.
    Keywords:  advanced materials; cancer cell-derived extracellular vesicles; cancer therapy; drug delivery; nanomedicine
    DOI:  https://doi.org/10.3389/fonc.2021.758884
  33. Front Immunol. 2021 ;12 746151
    Meta-Inflammation and Metabolic Reprogramming of Macrophages in Diabetes and Obesity: The Importance of Metabolites.
    Sara Russo, Marcel Kwiatkowski, Natalia Govorukhina, Rainer Bischoff, Barbro N Melgert.
      Diabetes mellitus type II and obesity are two important causes of death in modern society. They are characterized by low-grade chronic inflammation and metabolic dysfunction (meta-inflammation), which is observed in all tissues involved in energy homeostasis. A substantial body of evidence has established an important role for macrophages in these tissues during the development of diabetes mellitus type II and obesity. Macrophages can activate into specialized subsets by cues from their microenvironment to handle a variety of tasks. Many different subsets have been described and in diabetes/obesity literature two main classifications are widely used that are also defined by differential metabolic reprogramming taking place to fuel their main functions. Classically activated, pro-inflammatory macrophages (often referred to as M1) favor glycolysis, produce lactate instead of metabolizing pyruvate to acetyl-CoA, and have a tricarboxylic acid cycle that is interrupted at two points. Alternatively activated macrophages (often referred to as M2) mainly use beta-oxidation of fatty acids and oxidative phosphorylation to create energy-rich molecules such as ATP and are involved in tissue repair and downregulation of inflammation. Since diabetes type II and obesity are characterized by metabolic alterations at the organism level, these alterations may also induce changes in macrophage metabolism resulting in unique macrophage activation patterns in diabetes and obesity. This review describes the interactions between metabolic reprogramming of macrophages and conditions of metabolic dysfunction like diabetes and obesity. We also focus on different possibilities of measuring a range of metabolites intra-and extracellularly in a precise and comprehensive manner to better identify the subsets of polarized macrophages that are unique to diabetes and obesity. Advantages and disadvantages of the currently most widely used metabolite analysis approaches are highlighted. We further describe how their combined use may serve to provide a comprehensive overview of the metabolic changes that take place intracellularly during macrophage activation in conditions like diabetes and obesity.
    Keywords:  DMTII; M1; M2; MS; alternatively activated macrophage; classically activated macrophage; metabolic syndrome; metabolite analysis
    DOI:  https://doi.org/10.3389/fimmu.2021.746151
  34. Int J Mol Sci. 2021 Nov 17. pii: 12405. [Epub ahead of print]22(22):
    Nanoparticle-Mediated Delivery Systems in Photodynamic Therapy of Colorectal Cancer.
    Nokuphila Winifred Nompumelelo Simelane, Heidi Abrahamse.
      Colorectal cancer (CRC) involving a malignant tumour remains one of the greatest contributing causes of fatal mortality and has become the third globally ranked malignancy in terms of cancer-associated deaths. Conventional CRC treatment approaches such as surgery, radiation, and chemotherapy are the most utilized approaches to treat this disease. However, they are limited by low selectivity and systemic toxicity, so they cannot completely eradicate this disease. Photodynamic therapy (PDT) is an emerging therapeutic modality that exerts selective cytotoxicity to cancerous cells through the activation of photosensitizers (PSs) under light irradiation to produce cytotoxic reactive oxygen species (ROS), which then cause cancer cell death. Cumulative research findings have highlighted the significant role of traditional PDT in CRC treatment; however, the therapeutic efficacy of the classical PDT strategy is restricted due to skin photosensitivity, poor cancerous tissue specificity, and limited penetration of light. The application of nanoparticles in PDT can mitigate some of these shortcomings and enhance the targeting ability of PS in order to effectively use PDT against CRC as well as to reduce systemic side effects. Although 2D culture models are widely used in cancer research, they have some limitations. Therefore, 3D models in CRC PDT, particularly multicellular tumour spheroids (MCTS), have attracted researchers. This review summarizes several photosensitizers that are currently used in CRC PDT and gives an overview of recent advances in nanoparticle application for enhanced CRC PDT. In addition, the progress of 3D-model applications in CRC PDT is discussed.
    Keywords:  3D models; colorectal cancer; nanotechnology; photodynamic therapy; photosensitizers
    DOI:  https://doi.org/10.3390/ijms222212405
  35. Drug Metab Lett. 2021 ;14(2): 126-136
    The Role of Aldehyde Oxidase in the Metabolic Clearance of Substituted Benzothiazoles.
    Yohannes Teffera, Jingzhou Liu, Paul Krolikowski, Zhiyang Zhao.
       BACKGROUND: A group of substituted benzothiazoles from a research project was found to have low microsomal clearance. However, these compounds had very high clearance in vivo.
    METHODS: In the present study, the clearance mechanism of two of the structural analogs, was investigated in vitro and in vivo.
    RESULTS: In vitro studies showed the formation of corresponding non-P450 dependent oxidative metabolites in S9, cytosol, and hepatocytes. The in vitro formation of these metabolites was observed in mice, rats, non-human primates, and humans. The dog did not form the corresponding metabolites in any of the matrices. Inhibition studies with S9 fraction and incubation with human recombinant aldehyde oxidase (AO) showed that the formation of the corresponding metabolites was AO dependent. To investigate the role of this pathway in vivo, mice were dosed with compound A and bile and plasma were analyzed. Most of the metabolites in bile contained the AO-dependent oxidized benzothiazole moiety, indicating that metabolism involving AO was probably the main pathway for clearance. The same metabolites were also observed circulating in plasma. Mass spectrometric analysis of the metabolite showed that the oxidation was on the benzothiazole moiety, but the exact position could not be identified. Isolation of the metabolite of compound A and analysis by NMR confirmed the structure of the metabolite as C2 carbon oxidation of the thiazole ring resulting in carboxamide moiety. Further comparison of both metabolites with corresponding authentic standards confirmed the structures.
    CONCLUSION: To our knowledge, such an observation of in vitro and in vivo oxidation of substituted benzothiazole by AO has not been reported before. The results helped the medicinal chemists design compounds that avoid AO-mediated metabolism and with better ADME property.
    Keywords:  Aldehyde oxidase; clearance; in vitro metabolism; in vivo metabolism; metabolite identification.; substituted Benzothiazole
    DOI:  https://doi.org/10.2174/1872312814666210405101419
  36. Front Cell Dev Biol. 2021 ;9 760705
    Context Matters-Why We Need to Change From a One Size Fits all Approach to Made-to-Measure Therapies for Individual Patients With Pancreatic Cancer.
    Sushmitha Sankarasubramanian, Ulrike Pfohl, Christian R A Regenbrecht, Christoph Reinhard, Lena Wedeken.
      Pancreatic cancer is one of the deadliest cancers and remains a major unsolved health problem. While pancreatic ductal adenocarcinoma (PDAC) is associated with driver mutations in only four major genes (KRAS, TP53, SMAD4, and CDKN2A), every tumor differs in its molecular landscape, histology, and prognosis. It is crucial to understand and consider these differences to be able to tailor treatment regimens specific to the vulnerabilities of the individual tumor to enhance patient outcome. This review focuses on the heterogeneity of pancreatic tumor cells and how in addition to genetic alterations, the subsequent dysregulation of multiple signaling cascades at various levels, epigenetic and metabolic factors contribute to the oncogenesis of PDAC and compensate for each other in driving cancer progression if one is tackled by a therapeutic approach. This implicates that besides the need for new combinatorial therapies for PDAC, a personalized approach for treating this highly complex cancer is required. A strategy that combines both a target-based and phenotypic approach to identify an effective treatment, like Reverse Clinical Engineering® using patient-derived organoids, is discussed as a promising way forward in the field of personalized medicine to tackle this deadly disease.
    Keywords:  3D cell culture models; KRAS; combined targeted and phenotypic approach; pancreatic ductal adenocarcinoma (PDAC); patient-derived tumor organoids; personalized medicine; reverse clinical engineering; tumor heterogeneity
    DOI:  https://doi.org/10.3389/fcell.2021.760705
  37. Anticancer Agents Med Chem. 2021 Nov 18.
    Gallic acid: a dietary polyphenol that exhibits anti-neoplastic activities by modulating multiple oncogenic targets.
    Hardeep Singh Tuli, Hiral Mistry, Ginpreet Kaur, Diwakar Aggarwal, Vivek Kumar Garg, Sonam Mittal, Mükerrem Betül Yerer, Katrin Sak, Md Asaduzzaman Khan.
      Phytochemicals are being used for thousands of years to prevent dreadful malignancy. Side effects of existing allopathic treatment have also initiated intense research in the field of bioactive phytochemicals. Gallic acid, a natural polyphenolic compound, exists freely as well as in polymeric forms. The anti-cancer properties of gallic acid are indomitable by a variety of cellular pathways such as induction of programmed cell death, cell cycle apprehension, reticence of vasculature and tumor migration, and inflammation. Furthermore, gallic acid is found to show synergism with other existing chemotherapeutic drugs. Therefore, the antineoplastic role of gallic acid suggests its promising therapeutic candidature in the near future. The present review describes all these aspects of gallic acid at a single platform. In addition nanotechnology-mediated approaches are also discussed to enhance bioavailability and therapeutic efficacy.
    Keywords:  Gallic acid; anti-angiogenesis; anti-metastasis; anti-proliferation; apoptosis
    DOI:  https://doi.org/10.2174/1871520621666211119085834
  38. Cancers (Basel). 2021 Nov 15. pii: 5701. [Epub ahead of print]13(22):
    The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies.
    Robert Ramer, Felix Wittig, Burkhard Hinz.
      Despite the long history of cannabinoid use for medicinal and ritual purposes, an endogenous system of cannabinoid-controlled receptors, as well as their ligands and the enzymes that synthesise and degrade them, was only discovered in the 1990s. Since then, the endocannabinoid system has attracted widespread scientific interest regarding new pharmacological targets in cancer treatment among other reasons. Meanwhile, extensive preclinical studies have shown that cannabinoids have an inhibitory effect on tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition (EMT) and induce tumour cell apoptosis and autophagy as well as immune response. Appropriate cannabinoid compounds could moreover be useful for cancer patients as potential combination partners with other chemotherapeutic agents to increase their efficacy while reducing unwanted side effects. In addition to the direct activation of cannabinoid receptors through the exogenous application of corresponding agonists, another strategy is to activate these receptors by increasing the endocannabinoid levels at the corresponding pathological hotspots. Indeed, a number of studies accordingly showed an inhibitory effect of blockers of the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on tumour development and spread. This review summarises the relevant preclinical studies with FAAH and MAGL inhibitors compared to studies with cannabinoids and provides an overview of the regulation of the endocannabinoid system in cancer.
    Keywords:  FAAH inhibitors; MAGL inhibitors; angiogenesis; apoptosis; autophagy; cancer; cannabinoids; endocannabinoid system; metastasis; tumour cell invasion; tumour cell proliferation; tumour-immune interactions
    DOI:  https://doi.org/10.3390/cancers13225701
  39. Pharmaceutics. 2021 Oct 26. pii: 1788. [Epub ahead of print]13(11):
    Antitumor Immune Response Triggered by Metal-Based Photosensitizers for Photodynamic Therapy: Where Are We?
    Alain C Jung, Fabien Moinard-Butot, Chloé Thibaudeau, Gilles Gasser, Christian Gaiddon.
      Metal complexes based on transition metals have rich photochemical and photophysical properties that are derived from a variety of excited state electronic configurations triggered by visible and near-infrared light. These properties can be exploited to produce powerful energy and electron transfer processes that can lead to oxygen-(in)dependent photobiological activity. These principles are the basis of photodynamic therapy (PDT), which is a clinically approved treatment that offers a promising, effective, and noninvasive complementary treatment or even an alternative to treat several types of cancers. PDT is based on a reaction involving a photosensitizer (PS), light, and oxygen, which ultimately generates cytotoxic reactive oxygen species (ROS). However, skin photosensitivity, due to the accumulation of PSs in skin cells, has hampered, among other elements, its clinical development and application. Therefore, these is an increasing interest in the use of (metal-based) PSs that are more specific to tumor cells. This may increase efficacy and corollary decrease side-effects. To this end, metal-containing nanoparticles with photosensitizing properties have recently been developed. In addition, several studies have reported that the use of immunogenic/immunomodulatory metal-based nanoparticles increases the antitumor efficacy of immune-checkpoint inhibitor-based immunotherapy mediated by anti-PD-(L)1 or CTLA-4 antibodies. In this review, we discuss the main metal complexes used as PDT PSs. Lastly, we review the preclinical studies associated with metal-based PDT PSs and immunotherapies. This therapeutic association could stimulate PDT.
    Keywords:  cancer; immunogenic cell death; photodynamic therapy; transition metals
    DOI:  https://doi.org/10.3390/pharmaceutics13111788
  40. Metabolites. 2021 Nov 04. pii: 758. [Epub ahead of print]11(11):
    Metabolomics-Microbiome Crosstalk in the Breast Cancer Microenvironment.
    Mysoon M Al-Ansari, Reem H AlMalki, Lina A Dahabiyeh, Anas M Abdel Rahman.
      Breast cancer, the most frequent cancer diagnosed among females, is associated with a high mortality rate worldwide. Alterations in the microbiota have been linked with breast cancer development, suggesting the possibility of discovering disease biomarkers. Metabolomics has emerged as an advanced promising analytical approach for profiling metabolic features associated with breast cancer subtypes, disease progression, and response to treatment. The microenvironment compromises non-cancerous cells such as fibroblasts and influences cancer progression with apparent phenotypes. This review discusses the role of metabolomics in studying metabolic dysregulation in breast cancer caused by the effect of the tumor microenvironment on multiple cells such as immune cells, fibroblasts, adipocytes, etc. Breast tumor cells have a unique metabolic profile through the elevation of glycolysis and the tricarboxylic acid cycle metabolism. This metabolic profile is highly sensitive to microbiota activity in the breast tissue microenvironment. Metabolomics shows great potential as a tool for monitoring metabolic dysregulation in tissue and associating the findings with microbiome expression.
    Keywords:  breast cancer; metabolomics; microbiome; microenvironment
    DOI:  https://doi.org/10.3390/metabo11110758
  41. Pharmaceuticals (Basel). 2021 Oct 22. pii: 1069. [Epub ahead of print]14(11):
    Rutin (Bioflavonoid) as Cell Signaling Pathway Modulator: Prospects in Treatment and Chemoprevention.
    Pratibha Pandey, Fahad Khan, Huda A Qari, Mohammad Oves.
      Cancer is a complex ailment orchestrated by numerous intrinsic and extrinsic pathways. Recent research has displayed a deep interest in developing plant-based cancer therapeutics for better management of the disease and limited side effects. A wide range of plant-derived compounds have been reported for their anticancer potential in the quest of finding an effective therapeutic approach. Rutin (vitamin P) is a low-molecular weight flavonoid glycoside (polyphenolic compound), abundantly present in various vegetables, fruits (especially berries and citrus fruits), and medicinal herbs. Numerous studies have delineated several pharmacological properties of rutin such as its antiprotozoal, antibacterial, anti-inflammatory, antitumor, antiviral, antiallergic, vasoactive, cytoprotective, antispasmodic, hypolipidemic, antihypertensive, and antiplatelet properties. Specifically, rutin-mediated anticancerous activities have been reported in several cancerous cell lines, but the most common scientific evidence, encompassing several molecular processes and interactions, including apoptosis pathway regulation, aberrant cell signaling pathways, and oncogenic genes, has not been thoroughly studied. In this direction, we attempted to project rutin-mediated oncogenic pathway regulation in various carcinomas. Additionally, we also incorporated advanced research that has uncovered the notable potential of rutin in the modulation of several key cellular functions via interaction with mRNAs, with major emphasis on elucidating direct miRNA targets of rutin as well as the process needed to transform these approaches for developing novel therapeutic interventions for the treatment of several cancers.
    Keywords:  cancer; cell signaling pathways; miRNA; rutin; therapeutic potential
    DOI:  https://doi.org/10.3390/ph14111069
  42. Nutrients. 2021 Oct 27. pii: 3831. [Epub ahead of print]13(11):
    Polyphenols, the Healthy Brand of Olive Oil: Insights and Perspectives.
    Mauro Finicelli, Tiziana Squillaro, Umberto Galderisi, Gianfranco Peluso.
      Given their beneficial potential on human health, plant food bioactive molecules are important components influencing nutrition. Polyphenols have been widely acknowledged for their potentially protective role against several complex diseases. In particular, the polyphenols of olive oil (OOPs) emerge as the key components of many healthy diets and have been widely studied for their beneficial properties. The qualitative and quantitative profile defining the composition of olive oil phenolic molecules as well as their absorbance and metabolism once ingested are key aspects that need to be considered to fully understand the health potential of these molecules. In this review, we provide an overview of the key aspects influencing these variations by focusing on the factors influencing the biosynthesis of OOPs and the findings about their absorption and metabolism. Despite the encouraging evidence, the health potential of OOPs is still debated due to limitations in current studies. Clinical trials are necessary to fully understand and validate the beneficial effects of olive oil and OOPs on human health. We provide an update of the clinical trials based on olive oil and/or OOPs that aim to understand their beneficial effects. Tailored studies are needed to standardize the polyphenolic distribution and understand the variables associated with phenol-enriched OO. An in-depth knowledge of the steps that occur following polyphenol ingestion may reveal useful insights to be used in clinical settings for the prevention and treatment of many diseases.
    Keywords:  bioavailability; clinical trial; human health; metabolism; olive oil; polyphenols
    DOI:  https://doi.org/10.3390/nu13113831
  43. Front Cell Dev Biol. 2021 ;9 745177
    Natural Products for the Management of Castration-Resistant Prostate Cancer: Special Focus on Nanoparticles Based Studies.
    Rajeev K Singla, Chandragiri Siva Sai, Hitesh Chopra, Sahar Behzad, Himangini Bansal, Rajat Goyal, Rupesh K Gautam, Christos Tsagkaris, Shikha Joon, Shailja Singla, Bairong Shen.
      Prostate cancer is the most common type of cancer among men and the second most frequent cause of cancer-related mortality around the world. The progression of advanced prostate cancer to castration-resistant prostate cancer (CRPC) plays a major role in disease-associated morbidity and mortality, posing a significant therapeutic challenge. Resistance has been associated with the activation of androgen receptors via several mechanisms, including alternative dehydroepiandrosterone biosynthetic pathways, other androgen receptor activator molecules, oncogenes, and carcinogenic signaling pathways. Tumor microenvironment plays a critical role not only in the cancer progression but also in the drug resistance. Numerous natural products have shown major potential against particular or multiple resistance pathways as shown by in vitro and in vivo studies. However, their efficacy in clinical trials has been undermined by their unfavorable pharmacological properties (hydrophobic molecules, instability, low pharmacokinetic profile, poor water solubility, and high excretion rate). Nanoparticle formulations can provide a way out of the stalemate, employing targeted drug delivery, improved pharmacokinetic drug profile, and transportation of diagnostic and therapeutic agents via otherwise impermeable biological barriers. This review compiles the available evidence regarding the use of natural products for the management of CRPC with a focus on nanoparticle formulations. PubMed and Google Scholar search engines were used for preclinical studies, while ClinicalTrials.gov and PubMed were searched for clinical studies. The results of our study suggest the efficacy of natural compounds such as curcumin, resveratrol, apigenin, quercetin, fisetin, luteolin, kaempferol, genistein, berberine, ursolic acid, eugenol, gingerol, and ellagic acid against several mechanisms leading to castration resistance in preclinical studies, but fail to set the disease under control in clinical studies. Nanoparticle formulations of curcumin and quercetin seem to increase their potential in clinical settings. Using nanoparticles based on betulinic acid, capsaicin, sintokamide A, niphatenones A and B, as well as atraric acid seems promising but needs to be verified with preclinical and clinical studies.
    Keywords:  advanced stage cancer; anticancer nanoformulations; hormone-sensitive cancer; prostate cancer; site-targeted drug delivery
    DOI:  https://doi.org/10.3389/fcell.2021.745177
  44. Nutrients. 2021 Nov 01. pii: 3914. [Epub ahead of print]13(11):
    Vitamins as Possible Cancer Biomarkers: Significance and Limitations.
    Sascha Venturelli, Christian Leischner, Thomas Helling, Markus Burkard, Luigi Marongiu.
      The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as 'hidden hunger'), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.
    Keywords:  cancer biomarker; cancer risk; vitamin A; vitamin B complex; vitamin C; vitamin D; vitamin E; vitamin K
    DOI:  https://doi.org/10.3390/nu13113914
  45. Int J Biol Macromol. 2021 Nov 22. pii: S0141-8130(21)02500-9. [Epub ahead of print]
    Application of chitosan modified nanocarriers in breast cancer.
    Sunil Kumar Dubey, Tanya Bhatt, Mukta Agrawal, Ranendra Narayan Saha, Swarnlata Saraf, Shailendra Saraf, Amit Alexander.
      As per the WHO, every year around 2.1 million women are detected with breast cancer. It is one of the most invasive cancer in women and second most among all, contributing around 15% of death worldwide. The available anticancer therapies including chemo, radio, and hormone therapy are associated with a high load of reversible and irreversible adverse effects, limited therapeutic efficacy, and low chances of quality survival. To minimize the side effects, improving therapeutic potency and patient compliance promising targeted therapies are highly desirable. In this sequence, various nanocarriers and target modified systems have been explored by researchers throughout the world. Among these chitosan-based nanocarriers offers one of the most interesting, flexible, and biocompatible systems. The unique characteristics of chitosan like surface flexibility, biocompatibility, hydrophilicity, non-toxic and cost-effective behavior assist to overcome the inadequacy of existing therapy. The present review throws light on the successes, failures, and current status of chitosan modified novel techniques for tumor targeting of bioactives. It also emphasizes the molecular classification of breast cancer and current clinical development of novel therapies. The review compiles most relevant works of the past 10 years focusing on the application of chitosan-based nanocarrier against breast cancer.
    Keywords:  Breast Cancer; Chitosan nanoparticles; Curcumin; Doxorubicin; Gemcitabine; Tamoxifen
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.11.095
  46. Adv Healthc Mater. 2021 Nov 23. e2102017
    A Glutathione Activatable Photosensitizer for Combined Photodynamic and Gas Therapy under Red Light Irradiation.
    Ran Wang, Xiang Xia, Yanjun Yang, Xiang Rong, Ting Liu, Zehou Su, Xiaolong Zeng, Jianjun Du, Jiangli Fan, Wen Sun, Xiaojun Peng.
      Although photodynamic therapy (PDT) is a promising approach for cancer therapy, most existing photosensitizers lack selectivity for tumor cells and the overexpressed glutathione (GSH) in tumor cells reduces the PDT efficiency. Therefore, designing photosensitizers that can be selectively activated within tumor cells and combine PDT with other therapeutic modalities represents a route for precise and efficient anticancer treatment. Herein, we report an organic activatable photosensitizer, CyI-DNBS, bearing 2,4-dinitrobenzenesulfonate (DNBS) as the cage group. CyI-DNBS can be uptaken by cancer cells after which the cage group is selectively removed by the intracellular GSH, resulting in the generation of SO2 for gas therapy. The reaction also releases the activated photosensitizer, CyI-OH, that can produce singlet oxygen (1 O2 ) under red light irradiation. Therefore, CyI-DNBS targets cancer cells for both photodynamic and SO2 gas therapy treatments. The activatable photosensitizer provides a new approach for PDT and SO2 gas synergistic therapy and demonstrates excellent anticancer effect in vivo. This article is protected by copyright. All rights reserved.
    Keywords:  activatable photosensitizer; gas therapy; mitochondria-targeting; photodynamic therapy; red-light therapy
    DOI:  https://doi.org/10.1002/adhm.202102017
  47. Nutrients. 2021 Oct 30. pii: 3902. [Epub ahead of print]13(11):
    Per- and Polyfluoroalkyl Substance Exposure Combined with High-Fat Diet Supports Prostate Cancer Progression.
    Ozan Berk Imir, Alanna Zoe Kaminsky, Qian-Ying Zuo, Yu-Jeh Liu, Ratnakar Singh, Michael J Spinella, Joseph Irudayaraj, Wen-Yang Hu, Gail S Prins, Zeynep Madak Erdogan.
      Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals utilized in various industrial settings and include products such as flame retardants, artificial film-forming foams, cosmetics, and non-stick cookware, among others. Epidemiological studies suggest a link between increased blood PFAS levels and prostate cancer incidence, but the mechanism through which PFAS impact cancer development is unclear. To investigate the link between PFAS and prostate cancer, we evaluated the impact of metabolic alterations resulting from a high-fat diet combined with PFAS exposure on prostate tumor progression. We evaluated in vivo prostate cancer xenograft models exposed to perfluorooctane sulfonate (PFOS), a type of PFAS compound, and different diets to study the effects of PFAS on prostate cancer progression and metabolic activity. Metabolomics and transcriptomics were used to understand the metabolic landscape shifts upon PFAS exposure. We evaluated metabolic changes in benign or tumor cells that lead to epigenomic reprogramming and altered signaling, which ultimately increase tumorigenic risk and tumor aggressiveness. Our studies are the first in the field to provide new and clinically relevant insights regarding novel metabolic and epigenetic states as well as to support the future development of effective preventative and therapeutic strategies for PFAS-induced prostate cancers. Our findings enhance understanding of how PFAS synergize with high-fat diets to contribute to prostate cancer development and establish an important basis to mitigate PFAS exposure.
    Keywords:  PFAS; high-fat diet; metabolism; prostate cancer
    DOI:  https://doi.org/10.3390/nu13113902
  48. Front Cell Dev Biol. 2021 ;9 766978
    Vitamin D-Mediated Anti-cancer Activity Involves Iron Homeostatic Balance Disruption and Oxidative Stress Induction in Breast Cancer.
    Khuloud Bajbouj, Lina Sahnoon, Jasmin Shafarin, Abeer Al-Ali, Jibran Sualeh Muhammad, Asima Karim, Salman Y Guraya, Mawieh Hamad.
      Background: Vitamin D deficiency associates with high risk of breast cancer (BRCA) and increased cellular iron. Vitamin D exerts some of its anti-cancer effects by regulating the expression of key iron regulatory genes (IRGs). The association between vitamin D and cellular iron content in BRCA remains ambiguous. Herein, we addressed whether vitamin D signaling exerts a role in cellular iron homeostasis thereby affecting survival of breast cancer cells. Methods: Expression profile of IRGs in vitamin D-treated breast cancer cells was analyzed using publicly available transcriptomic datasets. After treatment of BRCA cell lines MCF-7 and MDA-MB-231 with the active form of vitamin D, labile iron content, IRGs protein levels, oxidative stress, and cell survival were evaluated. Results: Bioinformatics analysis revealed several IRGs as well as cellular stress relates genes were differentially expressed in BRCA cells. Vitamin D treatment resulted in cellular iron depletion and differentially affected the expression of key IRGs protein levels. Vitamin D treatment exerted oxidative stress induction and alteration in the cellular redox balance by increasing the synthesis of key stress-related markers. Collectively, these effects resulted in a significant decrease in BRCA cell survival. Conclusion: These findings suggest that vitamin D disrupts cellular iron homeostasis leading to oxidative stress induction and cell death.
    Keywords:  breast cancer; cell death; iron; oxidative stress; vitamin D
    DOI:  https://doi.org/10.3389/fcell.2021.766978
  49. Mar Drugs. 2021 Oct 21. pii: 594. [Epub ahead of print]19(11):
    Halophilic Carotenoids and Breast Cancer: From Salt Marshes to Biomedicine.
    Micaela Giani, Yoel Genaro Montoyo-Pujol, Gloria Peiró, Rosa María Martínez-Espinosa.
      Breast cancer is the leading cause of death among women worldwide. Over the years, oxidative stress has been linked to the onset and progression of cancer. In addition to the classical histological classification, breast carcinomas are classified into phenotypes according to hormone receptors (estrogen receptor-RE-/progesterone receptor-PR) and growth factor receptor (human epidermal growth factor receptor-HER2) expression. Luminal tumors (ER/PR-positive/HER2-negative) are present in older patients with a better outcome. However, patients with HER2-positive or triple-negative breast cancer (TNBC) (ER/PR/HER2-negative) subtypes still represent highly aggressive behavior, metastasis, poor prognosis, and drug resistance. Therefore, new alternative therapies have become an urgent clinical need. In recent years, anticancer agents based on natural products have been receiving huge interest. In particular, carotenoids are natural compounds present in fruits and vegetables, but algae, bacteria, and archaea also produce them. The antioxidant properties of carotenoids have been studied during the last years due to their potential in preventing and treating multiple diseases, including cancer. Although the effect of carotenoids on breast cancer during in vitro and in vivo studies is promising, clinical trials are still inconclusive. The haloarchaeal carotenoid bacterioruberin holds great promise to the future of biomedicine due to its particular structure, and antioxidant activity. However, much work remains to be performed to draw firm conclusions. This review summarizes the current knowledge on pre-clinical and clinical analysis on the use of carotenoids as chemopreventive and chemotherapeutic agents in breast cancer, highlighting the most recent results regarding the use of bacterioruberin from haloarchaea.
    Keywords:  antioxidant; bacterioruberin; breast cancer; carotenoids; oxidative stress; pro-oxidant
    DOI:  https://doi.org/10.3390/md19110594
  50. Membranes (Basel). 2021 Nov 07. pii: 858. [Epub ahead of print]11(11):
    The mTOR Pathway in Pluripotent Stem Cells: Lessons for Understanding Cancer Cell Dormancy.
    Bashar A Alhasan, Sergei A Gordeev, Aleksandra R Knyazeva, Kseniia V Aleksandrova, Boris A Margulis, Irina V Guzhova, Irina I Suvorova.
      Currently, the success of targeted anticancer therapies largely depends on the correct understanding of the dormant state of cancer cells, since it is increasingly regarded to fuel tumor recurrence. The concept of cancer cell dormancy is often considered as an adaptive response of cancer cells to stress, and, therefore, is limited. It is possible that the cancer dormant state is not a privilege of cancer cells but the same reproductive survival strategy as diapause used by embryonic stem cells (ESCs). Recent advances reveal that high autophagy and mTOR pathway reduction are key mechanisms contributing to dormancy and diapause. ESCs, sharing their main features with cancer stem cells, have a delicate balance between the mTOR pathway and autophagy activity permissive for diapause induction. In this review, we discuss the functioning of the mTOR signaling and autophagy in ESCs in detail that allows us to deepen our understanding of the biology of cancer cell dormancy.
    Keywords:  autophagy; cancer cell dormancy; embryonic diapause; embryonic stem cells; mTOR; pluripotency; pluripotent stem cells
    DOI:  https://doi.org/10.3390/membranes11110858
  51. Metabolites. 2021 Nov 20. pii: 792. [Epub ahead of print]11(11):
    Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective.
    Jacob King, Maya Patel, Sriram Chandrasekaran.
      Histone deacetylases (HDACs) are epigenetic enzymes that play a central role in gene regulation and are sensitive to the metabolic state of the cell. The cross talk between metabolism and histone acetylation impacts numerous biological processes including development and immune function. HDAC inhibitors are being explored for treating cancers, viral infections, inflammation, neurodegenerative diseases, and metabolic disorders. However, how HDAC inhibitors impact cellular metabolism and how metabolism influences their potency is unclear. Discussed herein are recent applications and future potential of systems biology methods such as high throughput drug screens, cancer cell line profiling, single cell sequencing, proteomics, metabolomics, and computational modeling to uncover the interplay between metabolism, HDACs, and HDAC inhibitors. The synthesis of new systems technologies can ultimately help identify epigenomic and metabolic biomarkers for patient stratification and the design of effective therapeutics.
    Keywords:  epigenome; gene regulation; histone acetylation; histone deacetylases; metabolomics; proteomics; transcriptomics
    DOI:  https://doi.org/10.3390/metabo11110792
  52. Cells. 2021 Oct 22. pii: 2841. [Epub ahead of print]10(11):
    Iron Metabolism in Pancreatic Beta-Cell Function and Dysfunction.
    Algerta Marku, Alessandra Galli, Paola Marciani, Nevia Dule, Carla Perego, Michela Castagna.
      Iron is an essential element involved in a variety of physiological functions. In the pancreatic beta-cells, being part of Fe-S cluster proteins, it is necessary for the correct insulin synthesis and processing. In the mitochondria, as a component of the respiratory chain, it allows the production of ATP and reactive oxygen species (ROS) that trigger beta-cell depolarization and potentiate the calcium-dependent insulin release. Iron cellular content must be finely tuned to ensure the normal supply but also to prevent overloading. Indeed, due to the high reactivity with oxygen and the formation of free radicals, iron excess may cause oxidative damage of cells that are extremely vulnerable to this condition because the normal elevated ROS production and the paucity in antioxidant enzyme activities. The aim of the present review is to provide insights into the mechanisms responsible for iron homeostasis in beta-cells, describing how alteration of these processes has been related to beta-cell damage and failure. Defects in iron-storing or -chaperoning proteins have been detected in diabetic conditions; therefore, the control of iron metabolism in these cells deserves further investigation as a promising target for the development of new disease treatments.
    Keywords:  Iron metabolism; beta-cell function; diabetes; reactive oxygen species
    DOI:  https://doi.org/10.3390/cells10112841
  53. Cells. 2021 Oct 29. pii: 2946. [Epub ahead of print]10(11):
    Decanoic Acid Stimulates Autophagy in D. discoideum.
    Eleanor C Warren, Pavol Kramár, Katie Lloyd-Jones, Robin S B Williams.
      Ketogenic diets, used in epilepsy treatment, are considered to work through reduced glucose and ketone generation to regulate a range of cellular process including autophagy induction. Recent studies into the medium-chain triglyceride (MCT) ketogenic diet have suggested that medium-chain fatty acids (MCFAs) provided in the diet, decanoic acid and octanoic acid, cause specific therapeutic effects independent of glucose reduction, although a role in autophagy has not been investigated. Both autophagy and MCFAs have been widely studied in Dictyostelium, with findings providing important advances in the study of autophagy-related pathologies such as neurodegenerative diseases. Here, we utilize this model to analyze a role for MCFAs in regulating autophagy. We show that treatment with decanoic acid but not octanoic acid induces autophagosome formation and modulates autophagic flux in high glucose conditions. To investigate this effect, decanoic acid, but not octanoic acid, was found to induce the expression of autophagy-inducing proteins (Atg1 and Atg8), providing a mechanism for this effect. Finally, we demonstrate a range of related fatty acid derivatives with seizure control activity, 4BCCA, 4EOA, and Epilim (valproic acid), also function to induce autophagosome formation in this model. Thus, our data suggest that decanoic acid and related compounds may provide a less-restrictive therapeutic approach to activate autophagy.
    Keywords:  4BCCA; 4EOA; Dictyostelium; autophagy; cancer; decanoic acid; epilepsy; medium-chain triglycerides
    DOI:  https://doi.org/10.3390/cells10112946
  54. Cancers (Basel). 2021 Nov 19. pii: 5817. [Epub ahead of print]13(22):
    Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy.
    Kerstin Skibbe, Ann-Kathrin Brethack, Annika Sünderhauf, Mohab Ragab, Annika Raschdorf, Maren Hicken, Heidi Schlichting, Joyce Preira, Jennifer Brandt, Darko Castven, Bandik Föh, René Pagel, Jens U Marquardt, Christian Sina, Stefanie Derer.
      To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that a nutritional intervention designed to reduce aerobic glycolysis may boost the EGFR-directed antibody (Ab)-based therapy of pre-existing colitis-driven colorectal carcinoma (CRC). CRC development was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) administration to C57BL/6 mice. AOM/DSS-treated mice were fed a glucose-free, high-protein diet (GFHPD) or an isoenergetic control diet (CD) in the presence or absence of an i.p. injection of an anti-EGFR mIgG2a or respective controls. AOM/DSS-treated mice on a GFHPD displayed a reduced systemic glucose metabolism associated with reduced oxidative phosphorylation (OXPHOS) complex IV expression and diminished tumor loads. Comparable but not additive to an anti-EGFR-Ab therapy, the GFHPD was accompanied by enhanced tumoral goblet cell differentiation and decreased colonic PD-L1 and splenic CD3ε, as well as PD-1 immune checkpoint expression. In vitro, glucose-free, high-amino acid culture conditions reduced proliferation but improved goblet cell differentiation of murine and human CRC cell lines MC-38 and HT29-MTX in combination with down-regulation of PD-L1 expression. We here found GFHPD to systemically dampen glycolysis activity, thereby reducing CRC progression with a similar efficacy to EGFR-directed antibody therapy.
    Keywords:  AOM/DSS; EGFR; PD-1; PD-L1; amino acid metabolism; colorectal cancer; goblet cell differentiation
    DOI:  https://doi.org/10.3390/cancers13225817
  55. Polymers (Basel). 2021 Nov 22. pii: 4036. [Epub ahead of print]13(22):
    Recent Advancement in Chitosan-Based Nanoparticles for Improved Oral Bioavailability and Bioactivity of Phytochemicals: Challenges and Perspectives.
    Syed Sarim Imam, Sultan Alshehri, Mohammed M Ghoneim, Ameeduzzafar Zafar, Omar Awad Alsaidan, Nabil K Alruwaili, Sadaf Jamal Gilani, Md Rizwanullah.
      The excellent therapeutic potential of a variety of phytochemicals in different diseases has been proven by extensive studies throughout history. However, most phytochemicals are characterized by a high molecular weight, poor aqueous solubility, limited gastrointestinal permeability, extensive pre-systemic metabolism, and poor stability in the harsh gastrointestinal milieu. Therefore, loading of these phytochemicals in biodegradable and biocompatible nanoparticles (NPs) might be an effective approach to improve their bioactivity. Different nanocarrier systems have been developed in recent decades to deliver phytochemicals. Among them, NPs based on chitosan (CS) (CS-NPs), a mucoadhesive, non-toxic, and biodegradable polysaccharide, are considered the best nanoplatform for the oral delivery of phytochemicals. This review highlights the oral delivery of natural products, i.e., phytochemicals, encapsulated in NPs prepared from a natural polymer, i.e., CS, for improved bioavailability and bioactivity. The unique properties of CS for oral delivery such as its mucoadhesiveness, non-toxicity, excellent stability in the harsh environment of the GIT, good solubility in slightly acidic and alkaline conditions, and ability to enhance intestinal permeability are discussed first, and then the outcomes of various phytochemical-loaded CS-NPs after oral administration are discussed in detail. Furthermore, different challenges associated with the oral delivery of phytochemicals with CS-NPs and future directions are also discussed.
    Keywords:  bioactivity; bioavailability; chitosan nanoparticles; mucoadhesion; phytochemicals
    DOI:  https://doi.org/10.3390/polym13224036
  56. Biomedicines. 2021 Nov 01. pii: 1591. [Epub ahead of print]9(11):
    Targeted Therapies in Cancer: To Be or Not to Be, Selective.
    Skye Montoya, Deborah Soong, Nina Nguyen, Maurizio Affer, Sailasya P Munamarty, Justin Taylor.
      Development of targeted therapies in recent years revealed several nonchemotherapeutic options for patients. Chief among targeted therapies is small molecule kinase inhibitors targeting key oncogenic signaling proteins. Through competitive and noncompetitive inhibition of these kinases, and therefore the pathways they activate, cancers can be slowed or completely eradicated, leading to partial or complete remissions for many cancer types. Unfortunately, for many patients, resistance to targeted therapies, such as kinase inhibitors, ultimately develops and can necessitate multiple lines of treatment. Drug resistance can either be de novo or acquired after months or years of drug exposure. Since resistance can be due to several unique mechanisms, there is no one-size-fits-all solution to this problem. However, combinations that target complimentary pathways or potential escape mechanisms appear to be more effective than sequential therapy. Combinations of single kinase inhibitors or alternately multikinase inhibitor drugs could be used to achieve this goal. Understanding how to efficiently target cancer cells and overcome resistance to prior lines of therapy became imperative to the success of cancer treatment. Due to the complexity of cancer, effective treatment options in the future will likely require mixing and matching these approaches in different cancer types and different disease stages.
    Keywords:  cancer; clinical trial inhibitors; combination drug therapies; multikinase inhibitors; receptor tyrosine kinases; resistance mechanisms; single kinase inhibitors; targeted therapies
    DOI:  https://doi.org/10.3390/biomedicines9111591
  57. Biochem Biophys Res Commun. 2021 Nov 12. pii: S0006-291X(21)01540-0. [Epub ahead of print]585 111-116
    Ketamine suppresses proliferation and induces ferroptosis and apoptosis of breast cancer cells by targeting KAT5/GPX4 axis.
    Huixin Li, Wei Liu, Xiaoyu Zhang, Feng Wu, Dan Sun, Zunyi Wang.
      Breast cancer (BC) serves as a prevalent and mortal malignancy among female globally. Ferroptosis, as an oxidative cell death that characterized by abnormal iron accumulation, plays critical role in cancer development. Ketamine is a rapid-acting anesthetic agent and has presented potential anti-tumor properties. However, the effect of Ketamine on breast cancer is still obscure. Here, we aimed to explore the function of Ketamine in the modulation of proliferation and ferroptosis of breast cancer cells. The cell viability of breast cancer cells was repressed by the treatment of Ketamine, while ferroptosis inhibitor ferrostatin 1 and apoptosis inhibitor ZVAD-FMK could restore the cell viability. The treatment of Ketamine significantly decreased the Edu-positive breast cancer cells and the colony formation numbers, and the treatment of ferrostatin 1 reversed the effect of Ketamine. We observed that the levels of ferroptosis markers, such as MDA, lipid ROS, and Fe2+ were increased by the treatment of Ketamine in breast cancer cells. Regarding to the mechanism, we found that Ketamine inhibited the expression of GPX4, an anti-ferroptosis factor, by attenuating KAT5 on the promoter region of GPX4, repressing the enrichment of histone H3 lysine 27 acetylation (H3K27ac) and RNA polymerase II (RNA pol II). The treatment of Ketamine reduced the cell viability and proliferation of breast cancer cells, in which the overexpression of KAT5 or GPX4 was able to restore the phenotypes. The treatment of Ketamine induced the levels of MDA, lipid ROS, and Fe2+, while KAT5 or GPX4 overexpression could reverse this effect in breast cancer cells. Thus, we concluded that Ketamine suppressed proliferation and induced ferroptosis of breast cancer cells by targeting KAT5/GPX4 axis. Ketamine may serve as a potential therapeutic strategy for breast cancer.
    Keywords:  Breast cancer; Ferroptosis; GPX4; KAT5; Ketamine; Potential therapeutic strategy
    DOI:  https://doi.org/10.1016/j.bbrc.2021.11.029
  58. Nutrients. 2021 Oct 23. pii: 3750. [Epub ahead of print]13(11):
    Kaempferol, Myricetin and Fisetin in Prostate and Bladder Cancer: A Systematic Review of the Literature.
    Felice Crocetto, Erika di Zazzo, Carlo Buonerba, Achille Aveta, Savio Domenico Pandolfo, Biagio Barone, Francesco Trama, Vincenzo Francesco Caputo, Luca Scafuri, Matteo Ferro, Vincenzo Cosimato, Ferdinando Fusco, Ciro Imbimbo, Giuseppe Di Lorenzo.
      Prostate and bladder cancer represent the two most frequently diagnosed genito-urinary malignancies. Diet has been implicated in both prostate and bladder cancer. Given their prolonged latency and high prevalence rates, both prostate and bladder cancer represent attractive candidates for dietary preventive measures, including the use of nutritional supplements. Flavonols, a class of flavonoids, are commonly found in fruit and vegetables and are known for their protective effect against diabetes and cardiovascular diseases. Furthermore, a higher dietary intake of flavonols was associated with a lower risk of both bladder and prostate cancer in epidemiological studies. In this systematic review, we gathered all available evidence supporting the anti-cancer potential of selected flavonols (kaempferol, fisetin and myricetin) against bladder and prostate cancer. A total of 21, 15 and 7 pre-clinical articles on bladder or prostate cancer reporting on kaempferol, fisetin and myricetin, respectively, were found, while more limited evidence was available from animal models and epidemiological studies or clinical trials. In conclusion, the available evidence supports the potential use of these flavonols in prostate and bladder cancer, with a low expected toxicity, thus providing the rationale for clinical trials that explore dosing, settings for clinical use as well as their use in combination with other pharmacological and non-pharmacological interventions.
    Keywords:  bladder cancer; fisetin; kaempferol; myricetin; prostate cancer
    DOI:  https://doi.org/10.3390/nu13113750
  59. Cells. 2021 Nov 03. pii: 3003. [Epub ahead of print]10(11):
    Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence.
    Yun Haeng Lee, Ji Yun Park, Haneur Lee, Eun Seon Song, Myeong Uk Kuk, Junghyun Joo, Sekyung Oh, Hyung Wook Kwon, Joon Tae Park, Sang Chul Park.
      Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases. In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.
    Keywords:  ROS; mitochondria; mitochondrial metabolic reprogramming; senescence amelioration
    DOI:  https://doi.org/10.3390/cells10113003
  60. Invest New Drugs. 2021 Nov 27.
    Advances in glioma-associated oncogene (GLI) inhibitors for cancer therapy.
    Meng Zhang, Lijuan Gao, Yiping Ye, Xiaoyu Li.
      The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells, which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. As an important component of the Hh signaling pathway, glioma-associated oncogene (GLI) acts as a key signal transmission hub for various signaling pathways in many tumors. Here, we review direct and indirect inhibitors of GLI; summarize the abundant active structurally diverse natural GLI inhibitors; and discuss how to better develop and utilize GLI inhibitors to solve the problem of drug resistance in tumors of interest. In summary, GLI inhibitors will be promising candidates for various cancer treatments.
    Keywords:  Crosstalk in GLI pathways; GLI code; GLI inhibitors; Hedgehog pathway; Natural products; Signal transmission hub
    DOI:  https://doi.org/10.1007/s10637-021-01187-2
  61. Pharmaceutics. 2021 Nov 12. pii: 1917. [Epub ahead of print]13(11):
    Stimuli Responsive Nitric Oxide-Based Nanomedicine for Synergistic Therapy.
    Yijun Zhao, Xumei Ouyang, Yongjun Peng, Shaojun Peng.
      Gas therapy has received widespread attention from the medical community as an emerging and promising therapeutic approach to cancer treatment. Among all gas molecules, nitric oxide (NO) was the first one to be applied in the biomedical field for its intriguing properties and unique anti-tumor mechanisms which have become a research hotspot in recent years. Despite the great progress of NO in cancer therapy, the non-specific distribution of NO in vivo and its side effects on normal tissue at high concentrations have impaired its clinical application. Therefore, it is important to develop facile NO-based nanomedicines to achieve the on-demand release of NO in tumor tissue while avoiding the leakage of NO in normal tissue, which could enhance therapeutic efficacy and reduce side effects at the same time. In recent years, numerous studies have reported the design and development of NO-based nanomedicines which were triggered by exogenous stimulus (light, ultrasound, X-ray) or tumor endogenous signals (glutathione, weak acid, glucose). In this review, we summarized the design principles and release behaviors of NO-based nanomedicines upon various stimuli and their applications in synergistic cancer therapy. We also discuss the anti-tumor mechanisms of NO-based nanomedicines in vivo for enhanced cancer therapy. Moreover, we discuss the existing challenges and further perspectives in this field in the aim of furthering its development.
    Keywords:  drug delivery; gas therapy; nanomedicine; nitric oxide; stimuli responsive
    DOI:  https://doi.org/10.3390/pharmaceutics13111917
  62. Pharmaceuticals (Basel). 2021 Oct 26. pii: 1082. [Epub ahead of print]14(11):
    Multiple Antitumor Molecular Mechanisms Are Activated by a Fully Synthetic and Stabilized Pharmaceutical Product Delivering the Active Compound Sulforaphane (SFX-01) in Preclinical Model of Human Glioblastoma.
    Alessandro Colapietro, Alessandra Rossetti, Andrea Mancini, Stefano Martellucci, Giuseppe Ocone, Fanny Pulcini, Leda Biordi, Loredana Cristiano, Vincenzo Mattei, Simona Delle Monache, Francesco Marampon, Giovanni Luca Gravina, Claudio Festuccia.
      Frequent relapses and therapeutic resistance make the management of glioblastoma (GBM, grade IV glioma), extremely difficult. Therefore, it is necessary to develop new pharmacological compounds to be used as a single treatment or in combination with current therapies in order to improve their effectiveness and reduce cytotoxicity for non-tumor cells. SFX-01 is a fully synthetic and stabilized pharmaceutical product containing the α-cyclodextrin that delivers the active compound 1-isothiocyanato-4-methyl-sulfinylbutane (SFN) and maintains biological activities of SFN. In this study, we verified whether SFX-01 was active in GBM preclinical models. Our data demonstrate that SFX-01 reduced cell proliferation and increased cell death in GBM cell lines and patient-derived glioma initiating cells (GICs) with a stem cell phenotype. The antiproliferative effects of SFX-01 were associated with a reduction in the stemness of GICs and reversion of neural-to-mesenchymal trans-differentiation (PMT) closely related to epithelial-to-mesenchymal trans-differentiation (EMT) of epithelial tumors. Commonly, PMT reversion decreases the invasive capacity of tumor cells and increases the sensitivity to pharmacological and instrumental therapies. SFX-01 induced caspase-dependent apoptosis, through both mitochondrion-mediated intrinsic and death-receptor-associated extrinsic pathways. Here, we demonstrate the involvement of reactive oxygen species (ROS) through mediating the reduction in the activity of essential molecular pathways, such as PI3K/Akt/mTOR, ERK, and STAT-3. SFX-01 also reduced the in vivo tumor growth of subcutaneous xenografts and increased the disease-free survival (DFS) and overall survival (OS), when tested in orthotopic intracranial GBM models. These effects were associated with reduced expression of HIF1α which, in turn, down-regulates neo-angiogenesis. So, SFX-01 may have potent anti-glioma effects, regulating important aspects of the biology of this neoplasia, such as hypoxia, stemness, and EMT reversion, which are commonly activated in this neoplasia and are responsible for therapeutic resistance and glioma recurrence. SFX-01 deserves to be considered as an emerging anticancer agent for the treatment of GBM. The possible radio- and chemo sensitization potential of SFX-01 should also be evaluated in further preclinical and clinical studies.
    Keywords:  GBM; SFX-01; epithelial-to-mesenchymal trans-differentiation (EMT); hypoxia; stemness and tumor recurrence; sulforaphane
    DOI:  https://doi.org/10.3390/ph14111082
  63. Metabolites. 2021 Oct 31. pii: 756. [Epub ahead of print]11(11):
    Urinary Metabolic Markers of Bladder Cancer: A Reflection of the Tumor or the Response of the Body?
    Greta Petrella, Giorgia Ciufolini, Riccardo Vago, Daniel Oscar Cicero.
      This work will review the metabolic information that various studies have obtained in recent years on bladder cancer, with particular attention to discovering biomarkers in urine for the diagnosis and prognosis of this disease. In principle, they would be capable of complementing cystoscopy, an invasive but nowadays irreplaceable technique or, in the best case, of replacing it. We will evaluate the degree of reproducibility that the different experiments have shown in the indication of biomarkers, and a synthesis will be attempted to obtain a consensus list that is more likely to become a guideline for clinical practice. In further analysis, we will inquire into the origin of these dysregulated metabolites in patients with bladder cancer. For this purpose, it will be helpful to compare the imbalances measured in urine with those known inside tumor cells or tissues. Although the urine analysis is sometimes considered a liquid biopsy because of its direct contact with the tumor in the bladder wall, it contains metabolites from all organs and tissues of the body, and the tumor is separated from urine by the most impermeable barrier found in mammals. The distinction between the specific and systemic responses can help understand the disease and its consequences in more depth.
    Keywords:  bladder cancer; diagnostic; metabolomics; prognostic; systemic response
    DOI:  https://doi.org/10.3390/metabo11110756
  64. Front Neurosci. 2021 ;15 756970
    Chronobiology and Metabolism: Is Ketogenic Diet Able to Influence Circadian Rhythm?
    Elena Gangitano, Lucio Gnessi, Andrea Lenzi, David Ray.
      Circadian rhythms underpin most physiological processes, including energy metabolism. The core circadian clock consists of a transcription-translation negative feedback loop, and is synchronized to light-dark cycles by virtue of light input from the retina, to the central clock in the suprachiasmatic nucleus in the hypothalamus. All cells in the body have circadian oscillators which are entrained to the central clock by neural and humoral signals. In addition to light entrainment of the central clock in the brain, it now emerges that other stimuli can drive circadian clock function in peripheral tissues, the major one being food. This can then drive the liver clock to be misaligned with the central brain clock, a situation of internal misalignment with metabolic disease consequences. Such misalignment is prevalent, with shift workers making up 20% of the working population. The effects of diet composition on the clock are not completely clarified yet. High-fat diet and fasting influence circadian expression of clock genes, inducing phase-advance and phase-delay in animal models. Ketogenic diet (KD) is able to induce a metabolic switch from carbohydrate to fatty acid oxidation, miming a fasting state. In recent years, some animal studies have been conducted to investigate the ability of the KD to modify circadian gene expression, and demonstrated that the KD alters circadian rhythm and induces a rearrangement of metabolic gene expression. These findings may lead to new approaches to obesity and metabolic pathologies treatment.
    Keywords:  chronobiology; circadian misalignment; circadian rhythm; ketogenic diet (KD); metabolism
    DOI:  https://doi.org/10.3389/fnins.2021.756970
  65. Life (Basel). 2021 Nov 05. pii: 1187. [Epub ahead of print]11(11):
    Target Nanoparticles against Pancreatic Cancer: Fewer Side Effects in Therapy.
    Jorge A Roacho-Pérez, Elsa N Garza-Treviño, Paulina Delgado-Gonzalez, Zuca G-Buentello, Juan Luis Delgado-Gallegos, Christian Chapa-Gonzalez, Margarita Sánchez-Domínguez, Celia N Sánchez-Domínguez, Jose Francisco Islas.
      Pancreatic cancer is the most common lethal tumor in America. This lethality is related to limited treatment options. Conventional treatments involve the non-specific use of chemotherapeutical agents such as 5-FU, capecitabine, gemcitabine, paclitaxel, cisplatin, oxaliplatin, or irinotecan, which produce several side effects. This review focuses on the use of targeted nanoparticles, such as metallic nanoparticles, polymeric nanoparticles, liposomes, micelles, and carbon nanotubes as an alternative to standard treatment for pancreatic cancer. The principal objective of nanoparticles is reduction of the side effects that conventional treatments produce, mostly because of their non-specificity. Several molecular markers of pancreatic cancer cells have been studied to target nanoparticles and improve current treatment. Therefore, properly functionalized nanoparticles with specific aptamers or antibodies can be used to recognize pancreatic cancer cells. Once cancer is recognized, these nanoparticles can attack the tumor by drug delivery, gene therapy, or hyperthermia.
    Keywords:  molecular markers; nanomedicine; pancreatic cancer; target therapy
    DOI:  https://doi.org/10.3390/life11111187
  66. Biomed Mater. 2021 Nov 26.
    Selective cytotoxicity mechanisms and biodistribution of diamond nanoparticles on the skin cancer in C57 mouse.
    Elham Moradi, Parvaneh Naserzadeh, Peiman Brouki Millan, Behnaz Ashtari.
      The cytotoxicity of diamond nanoparticles (DNs) to various cell lines has been on focus by numerous scientists. The cellular toxicity system of DNs has not been fully understood or explained in skin cancer, at this point. This research was carried out to discover and reveal the potential impacts of DNs on the secluded brain, heart, liver, kidney, and skin in addition to evaluation of their cytotoxicity mechanism under test conditions. Their biological activities, for example cell viability, the level of reactive oxygen species (ROS), lipid peroxidation, cytochrome c release and Apoptosis/Necrosis were evaluated. Additionally, the bio-distribution of these nanomaterials in tissues was examined in the C57 mouse. Relying on the findings of the investigation, DNs were found to increase the ROS level, MDA content, release of cytochrome c, and cell death in skin significantly compared to other groups. In the C57 mouse, DNs were observed to have accumulated in skin tissue more intensively than they did in other organs. The present study presents for the the proof that DNs can completely induce cell death signaling in skin cancer without bringing about a high cytotoxicity in other tissues. Results suggest that DNs can be valuable in recognition of skin cancer.
    Keywords:  Diamond Nanoparticles; Reactive Oxygen Species; Skin cancer; cell death signaling; cytotoxicity; stress oxidative
    DOI:  https://doi.org/10.1088/1748-605X/ac3d99
  67. J Agric Food Chem. 2021 Nov 23.
    Bisdemethoxycurcumin Promotes Apoptosis and Inhibits the Epithelial-Mesenchymal Transition through the Inhibition of the G-Protein-Coupled Receptor 161/Mammalian Target of Rapamycin Signaling Pathway in Triple Negative Breast Cancer Cells.
    Chun-Hung Chou, Hao-Kuang Wang, Ying-Chao Lin, Dai-Hua Tsai, Meng-Tien Lu, Chi-Tang Ho, You-Cheng Hseu, Hsin-Ling Yang, Tzong-Der Way.
      Triple negative breast cancer (TNBC) is one of the leading causes of cancer death in the world and lacks an effective targeted therapy. G-protein-coupled receptor 161 (GPR161) has been demonstrated to perform the functional regulations on TNBC progression and might be a potential new target for TNBC therapy. This study showed the effects of bisdemethoxycurcumin (BDMC) on GPR161 regulation, indicating that BDMC effectively inhibited GPR161 expression and downregulated GPR161-driven signaling. BDMC showed the potent inhibitory effects on TNBC proliferation through suppressing GPR161-mediated mammalian target of rapamycin (mTOR)/70 kDa ribosomal protein S6 kinase (p70S6K) activation. Besides, in this study, we discover the mechanism of GPR161-driven TNBC metastasis, linking to GPR161-mediated twist-related protein 1 (Twist1)/matrix metallopeptidase 9 (MMP9) contributing to the epithelial-mesenchymal transition (EMT). BDMC effectively repressed GPR161-mediated TNBC metastasis via inhibiting Twist1/MMP9-induced EMT. The three-dimensional invasion assay also showed that BDMC significantly inhibited TNBC invasion. The combination treatment of BDMC and rapamycin enhanced the inhibition of TNBC proliferation and metastasis through increasing the blockage of mTOR activation. Furthermore, this study also observed that BDMC activated the caspase 3/9 signaling pathway to induce TNBC apoptosis. Therefore, BDMC could be applicable to anticancer therapy, especially targeting on the GPR161-driven cancer type.
    Keywords:  G-protein-coupled receptor 161; Twist1/MMP9; bisdemethoxycurcumin; epithelial−mesenchymal transition; triple negative breast cancer
    DOI:  https://doi.org/10.1021/acs.jafc.1c05585
  68. Front Genet. 2021 ;12 749480
    Ten Reasons Why People With Down Syndrome are Protected From the Development of Most Solid Tumors -A Review.
    Marta Pilar Osuna-Marco, Mónica López-Barahona, Blanca López-Ibor, Águeda Mercedes Tejera.
      People with Down syndrome have unique characteristics as a result of the presence of an extra chromosome 21. Regarding cancer, they present a unique pattern of tumors, which has not been fully explained to date. Globally, people with Down syndrome have a similar lifetime risk of developing cancer compared to the general population. However, they have a very increased risk of developing certain tumors (e.g., acute leukemia, germ cell tumors, testicular tumors and retinoblastoma) and, on the contrary, there are some other tumors which appear only exceptionally in this syndrome (e.g., breast cancer, prostate cancer, medulloblastoma, neuroblastoma and Wilms tumor). Various hypotheses have been developed to explain this situation. The genetic imbalance secondary to the presence of an extra chromosome 21 has molecular consequences at several levels, not only in chromosome 21 but also throughout the genome. In this review, we discuss the different proposed mechanisms that protect individuals with trisomy 21 from developing solid tumors: genetic dosage effect, tumor suppressor genes overexpression, disturbed metabolism, impaired neurogenesis and angiogenesis, increased apoptosis, immune system dysregulation, epigenetic aberrations and the effect of different microRNAs, among others. More research into the molecular pathways involved in this unique pattern of malignancies is still needed.
    Keywords:  cancer; down syndrome; metabolism; microRNA; trisomy 21; tumor suppressor genes
    DOI:  https://doi.org/10.3389/fgene.2021.749480
  69. Pharmaceutics. 2021 Nov 19. pii: 1959. [Epub ahead of print]13(11):
    Role of Survivin in Bladder Cancer: Issues to Be Overcome When Designing an Efficient Dual Nano-Therapy.
    Maria Arista-Romero, Anna Cascante, Cristina Fornaguera, Salvador Borrós.
      Bladder cancer is the 10th most diagnosed cancer, with almost 10 M cancer deaths last year worldwide. Currently, chemotherapy is widely used as adjuvant therapy after surgical transurethral resection. Paclitaxel (PTX) is one of the most promising drugs, but cancer cells acquire resistance, causing failure of this treatment and increasing the recurrence of the disease. This poor chemotherapeutic response has been associated with the overexpression of the protein survivin. In this work, we present a novel dual nano-treatment for bladder cancer based on the hypothesis that the inhibition of survivin in cancer cells, using a siRNA gene therapy strategy, could decrease their resistance to PTX. For this purpose, two different polymeric nanoparticles were developed to encapsulate PTX and survivin siRNA independently. PTX nanoparticles showed sizes around 150 nm, with a paclitaxel loading of around 1.5%, that produced sustained tumor cell death. In parallel, siRNA nanoparticles, with similar sizes and loading efficiency of around 100%, achieved the oligonucleotide transfection and knocking down of survivin expression that also resulted in tumor cell death. However, dual treatment did not show the synergistic effect expected. The root cause of this issue was found to be the cell cycle arrest produced by nuclear survivin silencing, which is incompatible with PTX action. Therefore, we concluded that although the vastly reported role of survivin in bladder cancer, its silencing does not sensitize cells to currently applied chemotherapies.
    Keywords:  bladder cancer; combined nano-therapies; paclitaxel; polymeric nanoparticles; survivin
    DOI:  https://doi.org/10.3390/pharmaceutics13111959
  70. Medicines (Basel). 2021 Nov 10. pii: 69. [Epub ahead of print]8(11):
    Natural Products Induce Lysosomal Membrane Permeabilization as an Anticancer Strategy.
    Reginald Halaby.
      Cancer is a global health and economic issue. The majority of anticancer therapies become ineffective due to frequent genomic turnover and chemoresistance. Furthermore, chemotherapy and radiation are non-specific, killing all rapidly dividing cells including healthy cells. In this review, we examine the ability of some natural products to induce lysosomal-mediated cell death in neoplastic cells as a way to kill them more specifically than conventional therapies. This list is by no means exhaustive. We postulate mechanisms to explain lysosomal membrane permeabilization and its role in triggering cell death in cancer cells.
    Keywords:  apoptosis; cancer; lysosomal membrane permeabilization; lysosomes
    DOI:  https://doi.org/10.3390/medicines8110069
  71. Nutrients. 2021 Nov 11. pii: 4025. [Epub ahead of print]13(11):
    Onco-Preventive and Chemo-Protective Effects of Apple Bioactive Compounds.
    Linda Nezbedova, Tony McGhie, Mark Christensen, Julian Heyes, Noha Ahmed Nasef, Sunali Mehta.
      Cancer is one of the leading causes of death globally. Epidemiological studies have strongly linked a diet high in fruits to a lower incidence of cancer. Furthermore, extensive research shows that secondary plant metabolites known as phytochemicals, which are commonly found in fruits, have onco-preventive and chemo-protective effects. Apple is a commonly consumed fruit worldwide that is available all year round and is a rich source of phytochemicals. In this review, we summarize the association of apple consumption with cancer incidence based on findings from epidemiological and cohort studies. We further provide a comprehensive review of the main phytochemical patterns observed in apples and their bioavailability after consumption. Finally, we report on the latest findings from in vitro and in vivo studies highlighting some of the key molecular mechanisms targeted by apple phytochemicals in relation to inhibiting multiple 'hallmarks of cancer' that are important in the progression of cancer.
    Keywords:  antioxidants; apple; cancer; chemoprevention; fruit; phenolics; phytochemicals; triterpenoids
    DOI:  https://doi.org/10.3390/nu13114025
  72. Int J Mol Sci. 2021 Nov 13. pii: 12286. [Epub ahead of print]22(22):
    Treatment of HT29 Human Colorectal Cancer Cell Line with Nanocarrier-Encapsulated Camptothecin Reveals Histone Modifier Genes in the Wnt Signaling Pathway as Important Molecular Cues for Colon Cancer Targeting.
    Aisha Farhana, Avin Ee-Hwan Koh, Sangeetha Kothandan, Abdullah Alsrhani, Pooi Ling Mok, Suresh Kumar Subbiah.
      Cancer cells are able to proliferate in an unregulated manner. There are several mechanisms involved that propel such neoplastic transformations. One of these processes involves bypassing cell death through changes in gene expression and, consequently, cell growth. This involves a complex epigenetic interaction within the cell, which drives it towards oncogenic transformations. These epigenetic events augment cellular growth by potentially altering chromatin structures and influencing key gene expressions. Therapeutic mechanisms have been developed to combat this by taking advantage of the underlying oncogenic mechanisms through chemical modulation. Camptothecin (CPT) is an example of this type of drug. It is a selective topoisomerase I inhibitor that is effective against many cancers, such as colorectal cancer. Previously, we successfully formulated a magnetic nanocarrier-conjugated CPT with β-cyclodextrin and iron NPs (Fe3O4) cross-linked using EDTA (CPT-CEF). Compared to CPT alone, it boasts higher efficacy due to its selective targeting and increased solubility. In this study, we treated HT29 colon cancer cells with CPT-CEF and attempted to investigate the cytotoxic effects of the formulation through an epigenetic perspective. By using RNA-Seq, several differentially expressed genes were obtained (p < 0.05). Enrichr was then used for the over-representation analysis, and the genes were compared to the epigenetic roadmap and histone modification database. The results showed that the DEGs had a high correlation with epigenetic modifications involving histone H3 acetylation. Furthermore, a subset of these genes was shown to be associated with the Wnt/β-catenin signaling pathway, which is highly upregulated in a large number of cancer cells. These genes could be investigated as downstream therapeutic targets against the uncontrolled proliferation of cancer cells. Further interaction analysis of the identified genes with the key genes of the Wnt/β-catenin signaling pathway in colorectal cancer identified the direct interactors and a few transcription regulators. Further analysis in cBioPortal confirmed their genetic alterations and their distribution across patient samples. Thus, the findings of this study reveal that colorectal cancer could be reversed by treatment with the CPT-CEF nanoparticle-conjugated nanocarrier through an epigenetic mechanism.
    Keywords:  Wnt signaling pathway; bioinformatics; camptothecin; colorectal cancer; natural product
    DOI:  https://doi.org/10.3390/ijms222212286
  73. Biomolecules. 2021 Oct 29. pii: 1604. [Epub ahead of print]11(11):
    Targeting Hypoxia: Revival of Old Remedies.
    Nuria Vilaplana-Lopera, Maxym Besh, Eui Jung Moon.
      Tumour hypoxia is significantly correlated with patient survival and treatment outcomes. At the molecular level, hypoxia is a major driving factor for tumour progression and aggressiveness. Despite the accumulative scientific and clinical efforts to target hypoxia, there is still a need to find specific treatments for tumour hypoxia. In this review, we discuss a variety of approaches to alter the low oxygen tumour microenvironment or hypoxia pathways including carbogen breathing, hyperthermia, hypoxia-activated prodrugs, tumour metabolism and hypoxia-inducible factor (HIF) inhibitors. The recent advances in technology and biological understanding reveal the importance of revisiting old therapeutic regimens and repurposing their uses clinically.
    Keywords:  cancer; carbogen breathing; hyperthermia; hypoxia; tirapazamine; tumour metabolism
    DOI:  https://doi.org/10.3390/biom11111604
  74. Nutrients. 2021 Nov 04. pii: 3944. [Epub ahead of print]13(11):
    Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms.
    Manvi Sharma, Itika Arora, Min Chen, Huixin Wu, Michael R Crowley, Trygve O Tollefsbol, Yuanyuan Li.
      Consumption of dietary natural components such as genistein (GE) found in soy-rich sources is strongly associated with a lower risk of breast cancer. However, bioactive dietary component-based therapeutic strategies are largely understudied in breast cancer treatment. Our investigation sought to elucidate the potential mechanisms linking bioactive dietary GE to its breast cancer chemotherapeutic potential in a special subtype of aggressive breast cancer-triple-negative breast cancer (TNBC)-by utilizing two preclinical patient-derived xenograft (PDX) orthotopic mouse models: BCM-3204 and TM00091. Our study revealed that administration of GE resulted in a delay of tumor growth in both PDX models. With transcriptomics analyses in TNBC tumors isolated from BCM-3204 PDXs, we found that dietary soybean GE significantly influenced multiple tumor-regulated gene expressions. Further validation assessment of six candidate differentially expressed genes (DEGs)-Cd74, Lpl, Ifi44, Fzd9, Sat1 and Wwc1-demonstrated a similar trend at gene transcriptional and protein levels as observed in RNA-sequencing results. Mechanistically, GE treatment-induced Cd74 downregulation regulated the NF-κB/Bcl-xL/TAp63 signal pathway, which may contribute to soybean GE-mediated therapeutic effects on TNBC tumors. Additionally, our findings revealed that GE can modify expression levels of key epigenetic-associated genes such as DNA methyltransferases (Dnmt3b), ten-eleven translocation (Tet3) methylcytosine dioxygenases and histone deacetyltransferase (Hdac2), and their enzymatic activities as well as genomic DNA methylation and histone methylation (H3K9) levels. Collectively, our investigation shows high significance for potential development of a novel therapeutic approach by using bioactive soybean GE for TNBC patients who have few treatment options.
    Keywords:  RNA-seq; cancer therapy; epigenetic; genistein; patient-derived xenograft (PDX); triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.3390/nu13113944
  75. Nanomaterials (Basel). 2021 Nov 10. pii: 3013. [Epub ahead of print]11(11):
    Iron Oxide Nanoparticle-Based Hyperthermia as a Treatment Option in Various Gastrointestinal Malignancies.
    Julian Palzer, Lea Eckstein, Ioana Slabu, Oliver Reisen, Ulf P Neumann, Anjali A Roeth.
      Iron oxide nanoparticle-based hyperthermia is an emerging field in cancer treatment. The hyperthermia is primarily achieved by two differing methods: magnetic fluid hyperthermia and photothermal therapy. In magnetic fluid hyperthermia, the iron oxide nanoparticles are heated by an alternating magnetic field through Brownian and Néel relaxation. In photothermal therapy, the hyperthermia is mainly generated by absorption of light, thereby converting electromagnetic waves into thermal energy. By use of iron oxide nanoparticles, this effect can be enhanced. Both methods are promising tools in cancer treatment and are, therefore, also explored for gastrointestinal malignancies. Here, we provide an extensive literature research on both therapy options for the most common gastrointestinal malignancies (esophageal, gastric and colorectal cancer, colorectal liver metastases, hepatocellular carcinoma, cholangiocellular carcinoma and pancreatic cancer). As many of these rank in the top ten of cancer-related deaths, novel treatment strategies are urgently needed. This review describes the efforts undertaken in vitro and in vivo.
    Keywords:  cancer; iron oxide nanoparticles; magnetic fluid hyperthermia; photothermal therapy
    DOI:  https://doi.org/10.3390/nano11113013
  76. Mater Horiz. 2021 Feb 01. 8(2): 597-605
    Single nanosheet can sustainably generate oxygen and inhibit respiration simultaneously in cancer cells.
    Wei-Qiang Huang, Fei Wang, Ai-Zong Shen, Lei Zhang, Xuan Nie, Ze Zhang, Guang Chen, Lei Xia, Long-Hai Wang, Sheng-Gang Ding, Qing-Yong Meng, Wen-Jian Zhang, Chun-Yan Hong, Ye-Zi You.
      In a tumor, the abnormal cancer cell proliferation results in an insufficient O2 supply, and meanwhile cancer cells consume O2 very fast. The imbalance between a low oxygen supply and overwhelming oxygen consumption results in a low oxygen concentration in solid tumors. Therefore, in order to relieve hypoxia in tumors, it is necessary to not only sustainably generate O2, but also inhibit mitochondrial respiration simultaneously. Here, we found that a single Ti2C(OH)2 nanomaterial not only can sustainably generate O2 but also simultaneously highly inhibits mitochondrial respiration via binding phosphorylation proteins onto the surface in cancer cells. Ce6 was linked onto Ti2C(OH)2, forming Ti2C(OH)2-Ce6. Ti2C(OH)2-Ce6 could highly relieve hypoxia in tumors via the combination of sustainable O2 generation and respiration inhibition, produce enough 1O2 to kill cancer cells via PDT, and also effectively convert the absorbed light energy into thermal energy to kill cancer cell via PTT, thereby highly enhancing the cancer therapy.
    DOI:  https://doi.org/10.1039/d0mh01446j
  77. Biomedicines. 2021 Oct 23. pii: 1526. [Epub ahead of print]9(11):
    Ethoxyquin Inhibits the Progression of Murine Ehrlich Ascites Carcinoma through the Inhibition of Autophagy and LDH.
    Fekria Tayel, Magdy E Mahfouz, Afrah F Salama, Mohammed A Mansour.
      Cancer cells exhibit an increased glycolysis rate for ATP generation (the Warburg effect) to sustain an increased proliferation rate. In tumor cells, the oxidation of pyruvate in the Krebs cycle is substituted by lactate production, catalyzed by LDH. In this study, we use ethoxyquin (EQ) as a novel inhibitor to target LDH in murine Ehrlich ascites carcinoma (EAC) and as a combination therapy to improve the therapeutic efficacy of the conventional chemotherapy drug, cisplatin (CIS). We investigated the anti-tumor effect of EQ on EAC-bearing mice and checked whether EQ can sustain the anti-tumor potential of CIS and whether it influences LDH activity. Treatment with EQ had evident anti-tumor effects on EAC as revealed by the remarkable decrease in the expression of the anti-apoptotic gene Bcl-2 and by a significant increase in the expression of apoptotic genes (BAX and caspase-3). EQ also caused a significant decrease in the autophagic activity of EAC cells, as shown by a reduction in the fluorescence intensity of the autophagosome marker. Additionally, EQ restored the altered hematological and biochemical parameters and improved the disrupted hepatic tissues of EAC-bearing mice. Co-administration of EQ and CIS showed the highest anti-tumor effect against EAC. Collectively, our findings propose EQ as a novel inhibitor of LDH in cancer cells and as a combinatory drug to increase the efficacy of cisplatin. Further studies are required to validate this therapeutic strategy in different cancer models and preclinical trials.
    Keywords:  Ehrlich ascites carcinoma; LDH; autophagy; cisplatin; ethoxyquin; glycolysis
    DOI:  https://doi.org/10.3390/biomedicines9111526
  78. Front Chem. 2021 ;9 765552
    Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy.
    Paulina Wdowiak, Joanna Matysiak, Piotr Kuszta, Katarzyna Czarnek, Ewa Niezabitowska, Tomasz Baj.
      Cancer diseases remain major health problems in the world despite significant developments in diagnostic methods and medications. Many of the conventional therapies, however, have limitations due to multidrug resistance or severe side effects. Bladder cancer is a complex disorder, and can be classified according to its diverse genetic backgrounds and clinical features. A very promising direction in bladder cancer treatment is targeted therapy directed at specific molecular pathways. Derivatives of quinazolines constitute a large group of chemicals with a wide range of biological properties, and many quinazoline derivatives are approved for antitumor clinical use, e.g.,: erlotinib, gefitinib, afatinib, lapatinib, and vandetanib. The character of these depends mostly on the properties of the substituents and their presence and position on one of the cyclic compounds. Today, new quinazoline-based compounds are being designed and synthesized as potential drugs of anticancer potency against bladder cancers.
    Keywords:  anti-tumor activity; cancer cell lines; cancer treatment; quinazoline derivatives; urinary bladder cancer
    DOI:  https://doi.org/10.3389/fchem.2021.765552
  79. Antioxid Redox Signal. 2021 Nov 22.
    Tetrahydrobiopterin in cell function and death mechanisms.
    Jeannette Vásquez-Vivar, Zhongjie Shi, Sidhartha Tan.
       SIGNIFICANCE: Tetrahydrobiopterin is a required cofactor for enzymes regulating cellular redox homeostasis, aromatic amino acid metabolism, and neurotransmitter synthesis. Since these effects depend on the cofactor's availability, efforts to discover factors governing both its synthesis and recycling are necessary to elucidate cellular mechanisms of disease and therapeutic advances. Recent Advances: In most cells, tetrahydrobiopterin levels reflect the sum of synthetic and recycling enzyme activities. Enhanced expression of GTP-cyclohydrolase, the rate-limiting enzyme in the synthetic pathway, increases tetrahydrobiopterin, followed by a general improved cell function and survival. Increasing tetrahydrobiopterin levels using pharmacological approaches has similar beneficial effects, leading to enhanced production of neurotransmitters and nitric oxide or reducing oxidant species levels. At the cellular level, tetrahydrobiopterin counteracts anticancer therapies directed to enhance ferroptosis via GPX4 activity inhibition.
    CRITICAL ISSUES: A clear relationship between tetrahydrobiopterin and cell death is yet not well understood. The possibility that the cofactor directly influences cell viability has not been excluded in previous studies when modulating tetrahydrobiopterin-producing enzymes.
    FUTURE DIRECTIONS: The importance of cellular tetrahydrobiopterin variations and tetrahydrobiopterin biosynthetic enzymes to cell function and viability makes it essential to better characterize temporal changes, cofactor activity, and the influence on redox status, which in turn would help develop novel therapies.
    DOI:  https://doi.org/10.1089/ars.2021.0136
  80. J Invest Dermatol. 2021 Dec;pii: S0022-202X(21)02220-X. [Epub ahead of print]141(12): 2767-2774.e2
    Research Techniques Made Simple: Profiling Cellular Energy Metabolism.
    Mario Fabri, Matteo Villa, Michal A Stanczak, Joy Edwards-Hicks, Mauro Corrado, Erika L Pearce.
      The analysis of cellular metabolism is attracting increasing interest. Glycolysis and oxidative phosphorylation are intertwined with one another and dozens of other pathways to ultimately produce energy and maintain cellular fitness. However, cellular metabolism is much more than this. Metabolism underlies the proliferation, differentiation, and function of cells as well as the coordination of intercellular communication. Investigating metabolism allows the interpretation of cellular behavior in health and disease. In this article, we aim to demystify the complexity of cellular metabolism and explain the common approaches to study it. Whereas the analysis of cellular metabolism by western blot or flow cytometry might be accessible to most investigators, the functional and comprehensive analyses obtained with a Seahorse Analyzer or mass spectrometer come with monetary and logistical hurdles. We believe that the application of these techniques, together with collaborative efforts between scientists and clinicians, will uncover disease mechanisms and open novel therapeutic avenues for unmet clinical needs in the field of dermatology.
    DOI:  https://doi.org/10.1016/j.jid.2021.09.004
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