bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021‒11‒21
fifty-four papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. The Role of Succinic Acid Metabolism in Ovarian Cancer.
  2. The Pentose Phosphate Pathway in Cancer: Regulation and Therapeutic Opportunities.
  3. Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival.
  4. Ferroptosis-mediated Crosstalk in the Tumor Microenvironment Implicated in Cancer Progression and Therapy.
  5. Curcumin and resveratrol inhibit chemoresistance in cisplatin-resistant epithelial ovarian cancer cells via targeting P13K pathway.
  6. Contribution of branched chain amino acids to energy production and mevalonate synthesis in cancer cells.
  7. Quercetin Impact in Pancreatic Cancer: An Overview on Its Therapeutic Effects.
  8. Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
  9. Silencing of Pyruvate Kinase M2 via a Metal-Organic Framework Based Theranostic Gene Nanomedicine for Triple-Negative Breast Cancer Therapy.
  10. AKT1/HK2 Axis-mediated Glucose Metabolism: A Novel Therapeutic Target of Sulforaphane in Bladder Cancer.
  11. Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies.
  12. KRAS mutation: from undruggable to druggable in cancer.
  13. Fructose in the kidney: from physiology to pathology.
  14. Photosynthetic Oxygenation-Augmented Sonodynamic Nanotherapy of Hypoxic Tumor.
  15. Molecular insights on chemopreventive and anticancer potential of carvacrol: Implications from solid carcinomas.
  16. The Adroitness of Andrographolide as a Natural Weapon Against Colorectal Cancer.
  17. An updated review on pharmacological properties of neferine-A bisbenzylisoquinoline alkaloid from Nelumbo nucifera.
  18. Diosgenin a steroidal compound: An emerging way to cancer management.
  19. Agrimoniin sensitizes pancreatic cancer to apoptosis through ROS-mediated energy metabolism dysfunction.
  20. DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer.
  21. Jolkinolide B sensitizes bladder cancer to mTOR inhibitors via dual inhibition of Akt signaling and autophagy.
  22. Methionine synthase is essential for cancer cell proliferation in physiological folate environments.
  23. Redox regulation by carotenoids: evidence and conflicts for their application in cancer.
  24. A narrative review of mechanisms of ferroptosis in cancer: new challenges and opportunities.
  25. How Antimalarials and Antineoplastic Drugs can Interact in Combination Therapies: a Perspective on the Role of PPT1 Enzyme.
  26. Silk fibroin-capped metal-organic framework for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy.
  27. Role of Bioactive Constituents of Panax notoginseng in the Modulation of Tumorigenesis: A Potential Review for the Treatment of Cancer.
  28. Decellularized normal and cancer tissues as tools for cancer research.
  29. Capecitabine-induced leukoencephalopathy in a patient with triple-negative breast cancer: A case report and review of the literature.
  30. NSAIDs: Old Acquaintance in the Pipeline for Cancer Treatment and Prevention─Structural Modulation, Mechanisms of Action, and Bright Future.
  31. Harnessing the Combined Potential of Cancer Immunotherapy and Nanomedicine: A New Paradigm in Cancer Treatment.
  32. Copper complexes as antitumor agents: in vitro and in vivo evidences.
  33. Targeting long non coding RNA by natural products: Implications for cancer therapy.
  34. Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models.
  35. Size-dependent chemosensitization of doxorubicin-loaded polymeric nanoparticles for malignant glioma chemotherapy.
  36. Engineering Electronic Band Structure of Binary Thermoelectric Nanocatalysts for Augmented Pyrocatalytic Tumor Nanotherapy.
  37. Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.
  38. Systematic analysis of the lysine malonylome in Sanghuangporus sanghuang.
  39. Modern Approaches to Testing Drug Sensitivity of Patients' Tumors (Review).
  40. Implications of photodynamic cancer therapy: an overview of PDT mechanisms basically and practically.
  41. Generation of an Orthotopic Xenograft of Pancreatic Cancer Cells by Ultrasound-Guided Injection.
  42. Exploring phytochemicals from Himalayan medicinal plants as novel therapeutic agents.
  43. AIE material for photodynamic therapy.
  44. An updated review of folate-functionalized nanocarriers: a promising ligand in cancer.
  45. Therapeutic potential of curcumin in endometrial disorders: Current status and future perspectives.
  46. Enzyme-Responsive Materials as Carriers for Improving Photodynamic Therapy.
  47. Can Nanoparticles in Homeopathic Remedies Enhance Phototherapy of Cancer? A Hypothetical Model.
  48. Anticancer activity of oleanolic acid and its derivatives: Recent advances in evidence, target profiling and mechanisms of action.
  49. Can Ketogenic Diet Improve Alzheimer's Disease? Association With Anxiety, Depression, and Glutamate System.
  50. Promises of phytochemical based nano drug delivery systems in the management of cancer.
  51. Nanoscale delivery of phytochemicals targeting CRISPR/Cas9 for cancer therapy.
  52. Carbon nanomaterials as emerging nanotherapeutic platforms to tackle the rising tide of cancer - A review.
  53. Anticancer Properties and Pharmaceutical Applications of Ginsenoside Compound K: A Review.
  54. Localized disruption of redox homeostasis boosting ferroptosis of tumor by hydrogel delivery system.
  1. Front Oncol. 2021 ;11 769196
    The Role of Succinic Acid Metabolism in Ovarian Cancer.
    Lei Xia, Hairong Zhang, Xuezhen Wang, Xiaoyu Zhang, Ke Nie.
      Ovarian cancer is one of the most common malignancies and the highest mortality among gynecological malignancy. The standard therapy options for patients with ovarian cancer are cytoreductive surgery and chemotherapy, and although most patients do better with standard treatment, it is easy to relapse and be resistant to chemotherapy. Therefore, it is important to find new therapeutic strategies. More recently, metabolic reprogramming has been recognized as a hallmark of cancer and has become a potential target for tumor therapy. Mutations of metabolic enzymes are closely related to the development of ovarian cancer. The metabolic reprogramming of ovarian cancer not only provides energy to tumor cells, but also participates in various biological processes as signaling molecules. Succinic acid (SA) is an important metabolic intermediate involved in a number of metabolic pathways, such as TCA cycle and glutamine metabolism, and is also widely present in a variety of plants and vegetables. Studies show abnormal SA metabolism in many tumors and affect tumor formation through a variety of mechanisms. But the role of SA in ovarian cancer is less studied. This paper reviews the role of SA and its abnormal metabolic pathway in ovarian cancer.
    Keywords:  IDH; SDH; SUCNR1; glutamine; succinate acid
    DOI:  https://doi.org/10.3389/fonc.2021.769196
  2. Chemotherapy. 2021 Nov 12. 1-13
    The Pentose Phosphate Pathway in Cancer: Regulation and Therapeutic Opportunities.
    Noorhan Ghanem, Chirine El-Baba, Khaled Araji, Riyad El-Khoury, Julnar Usta, Nadine Darwiche.
      BACKGROUND: Tumorigenesis is associated with deregulation of nutritional requirements, intermediary metabolites production, and microenvironment interactions. Unlike their normal cell counterparts, tumor cells rely on aerobic glycolysis, through the Warburg effect.SUMMARY: The pentose phosphate pathway (PPP) is a major glucose metabolic shunt that is upregulated in cancer cells. The PPP comprises an oxidative and a nonoxidative phase and is essential for nucleotide synthesis of rapidly dividing cells. The PPP also generates nicotinamide adenine dinucleotide phosphate, which is required for reductive metabolism and to counteract oxidative stress in tumor cells. This article reviews the regulation of the PPP and discusses inhibitors that target its main pathways. Key Message: Exploiting the metabolic vulnerability of the PPP offers potential novel therapeutic opportunities and improves patients' response to cancer therapy.
    Keywords:  Cancer; Metabolism; Pentose phosphate pathway
    DOI:  https://doi.org/10.1159/000519784
  3. Oxid Med Cell Longev. 2021 ;2021 1341604
    Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival.
    Brittney Joy-Anne Foo, Jie Qing Eu, Jayshree L Hirpara, Shazib Pervaiz.
      Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.
    DOI:  https://doi.org/10.1155/2021/1341604
  4. Front Cell Dev Biol. 2021 ;9 739392
    Ferroptosis-mediated Crosstalk in the Tumor Microenvironment Implicated in Cancer Progression and Therapy.
    Yini Liu, Chunyan Duan, Rongyang Dai, Yi Zeng.
      Ferroptosis is a recently recognized form of non-apoptotic regulated cell death and usually driven by iron-dependent lipid peroxidation and has arisen to play a significant role in cancer biology. Distinct from other types of cell death in morphology, genetics, and biochemistry, ferroptosis is characterized by the accumulation of lipid peroxides and lethal reactive oxygen species controlled by integrated oxidant and antioxidant systems. Increasing evidence indicates that a variety of biological processes, including amino acid, iron, lactate, and lipid metabolism, as well as glutathione, phospholipids, NADPH, and coenzyme Q10 biosynthesis, are closely related to ferroptosis sensitivity. Abnormal ferroptotic response may modulate cancer progression by reprogramming the tumor microenvironment (TME). The TME is widely associated with tumor occurrence because it is the carrier of tumor cells, which interacts with surrounding cells through the circulatory and the lymphatic system, thus influencing the development and progression of cancer. Furthermore, the metabolism processes play roles in maintaining the homeostasis and evolution of the TME. Here, this review focuses on the ferroptosis-mediated crosstalk in the TME, as well as discussing the novel therapeutic strategies for cancer treatment.
    Keywords:  cancer progress; ferroptosis; immunity; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2021.739392
  5. Hum Exp Toxicol. 2021 Nov 18. 9603271211052985
    Curcumin and resveratrol inhibit chemoresistance in cisplatin-resistant epithelial ovarian cancer cells via targeting P13K pathway.
    Yalikun Muhanmode, Wen Mengke, Amina Maitinuri, Guqun Shen.
      BACKGROUND: The activation of the PI3K/AKT/mTOR pathway has been proved to be associated with survival as well as proliferation of various tumour cells in multiple cancer types, including epithelial ovarian cancer (EOC).PURPOSE: Moreover, the activation of the PI3K/AKT/mTOR pathway is the key mechanism responsible for higher invasiveness and migratory capacities of ovarian cancer cells. Furthermore, PI3K is crucial for activation of the PI3K/AKT/mTOR pathway; therefore, its inhibition might be an effective strategy against cancer.
    RESEARCH DESIGN: The combination approach is now an established strategy against cancer. So, the present study evaluated molecular mechanics behind the synergistic effects of curcumin and resveratrol along with cisplatin treatment on inhibition of the PI3K pathway in ovarian cancer cells.
    RESULTS: The present study confirmed significant inhibition of the PI3K/AKT/mTOR pathway as observed by Matrigel invasion assay, Western blot expression of important molecular markers and apoptotic markers.
    CONCLUSION:  The present study concludes that the combination of curcumin and resveratrol significantly sensitized the EOC cells to cisplatin treatment, thereby inhibiting chemoresistance in ovarian cancer cells by significant inhibition of the PI3K/AKT/mTOR pathway.
    Keywords:  AKT; Ovarian cancer; cisplatin; curcumin; p13k; resveratrol
    DOI:  https://doi.org/10.1177/09603271211052985
  6. Biochem Biophys Res Commun. 2021 Nov 12. pii: S0006-291X(21)01545-X. [Epub ahead of print]585 61-67
    Contribution of branched chain amino acids to energy production and mevalonate synthesis in cancer cells.
    Valeryia Mikalayeva, Monika Pankevičiūtė, Vaidotas Žvikas, V Arvydas Skeberdis, Sergio Bordel.
      Leucine, isoleucine and valine, known as branched chain amino acids (BCAAs), have been reported to be degraded by different cancer cells, and their biodegradation pathways have been suggested as anticancer targets. However, the mechanisms by which the degradation of BCAAs could support the growth of cancer cells remains unclear. In this work, 13C experiments have been carried out in order to elucidate the metabolic role of BCAA degradation in two breast cancer cell lines (MCF-7 and BCC). The results revealed that up to 36% of the energy production via respiration by MCF-7 cells was supported by the degradation of BCAAs. Also, 67% of the mevalonate (the precursor of cholesterol) synthesized by the cells was coming from the degradation of leucine. The results were lower for BCC cells (14 and 30%, respectively). The non-tumorigenic epythelial cell line MCF-10A was used as a control, showing that 10% of the mitochondrial acetyl-CoA comes from the degradation of BCAAs and no mevalonate production. Metabolic flux analysis around the mevalonate node, also revealed that significant amounts of acetoacetate are being produced from BCAA derived carbon, which could be at the source of lipid synthesis. From these results we can conclude that the degradation of BCAAs is an important energy and carbon source for the proliferation of some cancer cells and its therapeutic targeting could be an interesting option.
    Keywords:  Branched chain amino-acids; Cancer metabolism; Metabolic flux analysis
    DOI:  https://doi.org/10.1016/j.bbrc.2021.11.034
  7. Oxid Med Cell Longev. 2021 ;2021 4393266
    Quercetin Impact in Pancreatic Cancer: An Overview on Its Therapeutic Effects.
    Parina Asgharian, Abbas Pirpour Tazehkand, Saiedeh Razi Soofiyani, Kamran Hosseini, Miquel Martorell, Vahideh Tarhriz, Hossein Ahangari, Natália Cruz-Martins, Javad Sharifi-Rad, Zainab M Almarhoon, Alibek Ydyrys, Ablaikhanova Nurzhanyat, Arailym Yessenbekova, William C Cho.
      Pancreatic cancer (PC) is a lethal malignancy cancer, and its mortality rates have been increasing worldwide. Diagnosis of this cancer is complicated, as it does not often present symptoms, and most patients present an irremediable tumor having a 5-year survival rate after diagnosis. Regarding treatment, many concerns have also been raised, as most tumors are found at advanced stages. At present, anticancer compounds-rich foods have been utilized to control PC. Among such bioactive molecules, flavonoid compounds have shown excellent anticancer abilities, such as quercetin, which has been used as an adjunctive or alternative drug to PC treatment by inhibitory or stimulatory biological mechanisms including autophagy, apoptosis, cell growth reduction or inhibition, EMT, oxidative stress, and enhancing sensitivity to chemotherapy agents. The recognition that this natural product has beneficial effects on cancer treatment has boosted the researchers' interest towards more extensive studies to use herbal medicine for anticancer purposes. In addition, due to the expensive cost and high rate of side effects of anticancer drugs, attempts have been made to use quercetin but also other flavonoids for preventing and treating PC. Based on related studies, it has been found that the quercetin compound has significant effect on cancerous cell lines as well as animal models. Therefore, it can be used as a supplementary drug to treat a variety of cancers, particularly pancreatic cancer. This review is aimed at discussing the therapeutic effects of quercetin by targeting the molecular signaling pathway and identifying antigrowth, cell proliferation, antioxidative stress, EMT, induction of apoptotic, and autophagic features.
    DOI:  https://doi.org/10.1155/2021/4393266
  8. Autophagy. 2021 Nov 15. 1-3
    Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
    Payel Mondal, Christina Towers.
      Mitochondria are critical organelles that maintain cellular metabolism and overall function. The catabolic pathway of autophagy plays a central role in recycling damaged mitochondria. Although the autophagy pathway is indispensable for some cancer cell survival, our latest study shows that rare autophagy-dependent cancer cells can adapt to loss of this core pathway. In the process, the autophagy-deficient cells acquire unique dependencies on alternate forms of mitochondrial homeostasis. These rare autophagy-deficient clones circumvent the lack of canonical autophagy by increasing mitochondrial dynamics and by recycling damaged mitochondria via mitochondrial-derived vesicles (MDVs). These studies are the first to implicate MDVs in cancer cell metabolism although many unanswered questions remain about this non-canonical pathway.
    Keywords:  Cancer; mitochondrial fusion; mitochondrial-derived vesicles; mitophagy; non-canonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1999562
  9. ACS Appl Mater Interfaces. 2021 Nov 19.
    Silencing of Pyruvate Kinase M2 via a Metal-Organic Framework Based Theranostic Gene Nanomedicine for Triple-Negative Breast Cancer Therapy.
    Siming Huang, Wangshu Zhu, Fang Zhang, Guosheng Chen, Xiaoxue Kou, Xieqing Yang, Gangfeng Ouyang, Jun Shen.
      Triple-negative breast cancer (TNBC) is typically associated with poor prognosis due to its only partial response to chemotherapy and lack of clinically established targeted therapies coupled with an aggressive disease course. Aerobic glycolysis is a hallmark of reprogrammed metabolic activity in cancer cells, which can be repressed by small-interfering RNA (siRNA). However, the lack of effective carriers to deliver vulnerable siRNA restricts the clinical potentials of glycolysis-based gene therapy for TNBC. Herein, we develop a tumor-targeted, biomimetic manganese dioxide (MnO2)-shrouded metal-organic framework (MOF) based nanomedicine to deliver siRNA against pyruvate kinase muscle isozyme M2 (siPKM2), wherein PKM2 is a rate-limiting enzyme in glycolysis, to inhibit the reprogrammed glycolysis of TNBC. This MOF-based genetic nanomedicine shows excellent monodispersity and stability and protects siPKM2 against degradation by nucleases. The nanomedicine not only substantially blocks the glycolytic pathway but also improves intracellular hypoxia in TNBC cells, with a resultant O2-enhanced anticancer effect. In the mice orthotopic TNBC model, the nanomedicine shows a remarkable therapeutic effect. Meanwhile, the Mn2+ ions released from acid microenvironment-responsive MnO2 enable in vivo monitoring of the therapeutic process with magnetic resonance imaging (MRI). Our study shows great promise with this MRI-visible MOF-based nanomedicine for treating TNBC by inhibition of glycolysis via the RNA interference.
    Keywords:  glycolysis; magnetic resonance imaging; metal−organic frameworks; small-interfering RNA; triple-negative breast cancer
    DOI:  https://doi.org/10.1021/acsami.1c18053
  10. Mol Nutr Food Res. 2021 Nov 17. e2100738
    AKT1/HK2 Axis-mediated Glucose Metabolism: A Novel Therapeutic Target of Sulforaphane in Bladder Cancer.
    Lei Huang, Canxia He, Sicong Zheng, Chao Wu, Minghua Ren, Yujuan Shan.
      SCOPE: Metabolic disorder is a pivotal hallmark of cancer cells. Sulforaphane (SFN) is reported to improve lipid metabolism. However, the effect of SFN on glucose metabolism in bladder cancer remains unclear. Hence, we investigated the effect and underling mechanism.METHODS AND RESULTS: We collected biological samples from bladder cancer patients, and also investigated using N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder cancer mice and bladder cancer cell lines. A novel glucose transport aberrant-independent aerobic glycolysis was found in bladder cancer patients, and the lower malignancy tissues have the more obvious abnormality. SFN strongly down-regulated ATP production by inhibiting glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). Both in vitro cell culture and in bladder tumor mice, SFN weakened the glycolytic flux by suppressing multiple metabolic enzymes, including hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH). Moreover, SFN decreased the level of AKT1 and p-AKT ser473 , especially in low-invasive UMUC3 cells. The down-regulation of ATP and HK2 by SFN were both reversed by AKT1 overexpression.
    CONCLUSIONS: SFN down-regulated the unique glucose transport aberrant-independent aerobic glycolysis existed in bladder cancer via blocking the AKT1/HK2 axis and PDH expression. This article is protected by copyright. All rights reserved.
    Keywords:  aerobic glycolysis; bladder cancer; glucose metabolism; glycolysis; sulforaphane
    DOI:  https://doi.org/10.1002/mnfr.202100738
  11. Front Oncol. 2021 ;11 743006
    Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies.
    Yan Zhao, Zineng Huang, Hongling Peng.
      Cell death is essential for the normal metabolism of human organisms. Ferroptosis is a unique regulated cell death (RCD) mode characterized by excess accumulation of iron-dependent lipid peroxide and reactive oxygen species (ROS) compared with other well-known programmed cell death modes. It has been currently recognized that ferroptosis plays a rather important role in the occurrence, development, and treatment of traumatic brain injury, stroke, acute kidney injury, liver damage, ischemia-reperfusion injury, tumor, etc. Of note, ferroptosis may be explained by the expression of various molecules and signaling components, among which iron, lipid, and amino acid metabolism are the key regulatory mechanisms of ferroptosis. Meanwhile, tumor cells of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma (MM), are identified to be sensitive to ferroptosis. Targeting potential regulatory factors in the ferroptosis pathway may promote or inhibit the disease progression of these malignancies. In this review, a systematic summary was conducted on the key molecular mechanisms of ferroptosis and the current potential relationships of ferroptosis with leukemia, lymphoma, and MM. It is expected to provide novel potential therapeutic approaches and targets for hematological malignancies.
    Keywords:  GSH; ferroptosis; iron metabolism; leukemia; lymphoma; reactive oxygen species; regulated cell death
    DOI:  https://doi.org/10.3389/fonc.2021.743006
  12. Signal Transduct Target Ther. 2021 Nov 15. 6(1): 386
    KRAS mutation: from undruggable to druggable in cancer.
    Lamei Huang, Zhixing Guo, Fang Wang, Liwu Fu.
      Cancer is the leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. However, KRAS has been deemed a challenging therapeutic target, even "undruggable", after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have obtained encouraging results in clinical trials. Excitingly, AMG510 was the first drug-targeting KRAS (G12C) to be approved for clinical use this year. This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment.
    DOI:  https://doi.org/10.1038/s41392-021-00780-4
  13. Kidney Res Clin Pract. 2021 Nov 01.
    Fructose in the kidney: from physiology to pathology.
    Takahiko Nakagawa, Duk-Hee Kang.
      The Warburg effect is a unique property of cancer cells, in which glycolysis is activated instead of mitochondrial respiration despite oxygen availability. However, recent studies found that the Warburg effect also mediates non-cancer disorders, including kidney disease. Currently, diabetes or glucose has been postulated to mediate the Warburg effect in the kidney, but it is of importance that the Warburg effect can be induced under nondiabetic conditions. Fructose is endogenously produced in several organs, including the kidney, under both physiological and pathological conditions. In the kidney, fructose is predominantly metabolized in the proximal tubules; under normal physiologic conditions, fructose is utilized as a substrate for gluconeogenesis and contributes to maintain systemic glucose concentration under starvation conditions. However, when present in excess, fructose likely becomes deleterious, possibly due in part to excessive uric acid, which is a by-product of fructose metabolism. A potential mechanism is that uric acid suppresses aconitase in the Krebs cycle and therefore reduces mitochondrial oxidation. Consequently, fructose favors glycolysis over mitochondrial respiration, a process that is similar to the Warburg effect in cancer cells. Activation of glycolysis also links to several side pathways, including the pentose phosphate pathway, hexosamine pathway, and lipid synthesis, to provide biosynthetic precursors as fuel for renal inflammation and fibrosis. We now hypothesize that fructose could be the mediator for the Warburg effect in the kidney and a potential mechanism for chronic kidney disease.
    Keywords:  Fructose; Glycolysis; Inflammation; Mitochondria; Proximal tubules; Uric acid; Warburg effect
    DOI:  https://doi.org/10.23876/j.krcp.21.138
  14. Adv Healthc Mater. 2021 Nov 17. e2102135
    Photosynthetic Oxygenation-Augmented Sonodynamic Nanotherapy of Hypoxic Tumor.
    Shuting Lu, Wei Feng, Caihong Dong, Xinran Song, Xiang Gao, Jinhe Guo, Yu Chen, Zhongqian Hu.
      Reactive oxygen species (ROS) has been employed as a powerful therapeutic agent for eradicating tumor via oxidative stress. As an emerging ROS-involving noninvasive anticancer therapeutic modality, sonodynamic therapy (SDT) with high tissue penetration depth and benign remote spatiotemporal selectivity has been progressively utilized as the distinct alternative for ROS-based tumor treatment. However, the hypoxic tumor microenvironment substantially restricts the sonodynamic effect. In this work, an oxygen self-sufficient hybrid sonosensitizer on the basis of photosynthetic microorganisms cyanobacteria (Cyan) integrated with ultrasmall oxygen-deficient bimetallic oxide Mn1.4 WOx nanosonosensitizers, termed as M@C, is designed and engineered to overcome the critical issue of hypoxia-induced tumor resistance and strengthen the SDT effect. The sustained photosynthetic oxygen production by Cyan under light illumination can promote Mn1.4 WOx nanosonosensitizers to produce more ROS against cancer cells both in vitro and in vivo under ultrasound (US) irradiation. Especially, the sustained oxygen evolution for suppressing the gene expression of hypoxia-inducible factor 1alpha (HIF-1α) further boosts and augments the SDT efficiency. Thus, this work provides the paradigm that the rationally engineered biohybrid microorganism-based multifunctional sonosensitizers can serve as an effective bioplatform for augmenting the therapeutic efficiency of SDT, particularly for the treatment of hypoxic tumors. This article is protected by copyright. All rights reserved.
    Keywords:  ROS; cyanobacteria; hybrid sonosensitizer; sonodynamic therapy; tumor hypoxia microenvironment
    DOI:  https://doi.org/10.1002/adhm.202102135
  15. J Food Biochem. 2021 Nov 18. e14010
    Molecular insights on chemopreventive and anticancer potential of carvacrol: Implications from solid carcinomas.
    Afza Ahmad, Mohd Saeed, Irfan A Ansari.
      Globally, cancer is one of the deadliest diseases, estimated to cause 9.9 million deaths in 2020. Conventional cancer treatments commonly involve mono-chemotherapy or a combination of radiotherapy and mono-chemotherapy. However, the negative side effects of these approaches have been extensively reported and have prompted the search for new therapeutic drugs. Over the past few years, numerous dietary agents, medicinal plants, and their phytochemicals gained considerable therapeutic importance because of their anticancer, antiviral, anti-inflammatory, and antioxidant activities. Recent years have shown that essential oils possess therapeutic effects against numerous cancers. They are primarily used due to their lesser side effects than standard chemotherapeutic drugs. Carvacrol (CRV) is a phenolic monoterpenoid found in essential oils of oregano, thyme, pepperwort, wild bergamot, and other plants. Numerous anticancer reports of CRV substantiated that the main mechanistic action of CRV involves reduction in the viability of cancer cells and induction of apoptosis via both intrinsic and extrinsic pathways. CRV also obstructs the migration and invasion of cells leading to the suppressed proliferation rate. Furthermore, CRV mediates augmented ROS generation resulting in DNA damage and also halts the progression of cell cycle. Treatment of CRV modulates the expression of apoptotic proteins (Bax, Bad) and molecular targets of various signaling pathways (PI3K/AKT/mTOR, MAPKs, and Notch) in multiple solid carcinomas. Hence, this review aimed to acquire and disseminate the knowledge of chemopreventive and anticancer effects of CRV and the mechanisms of action already described for the compound against numerous cancers, including solid carcinomas, to guide future research. PRACTICAL APPLICATIONS: Development and formulation of phytocompound based anticancer drug agents to counteract the aftereffects of chemotherapeutic drugs is a propitious approach. CRV is a monoterpenoid consisting of a phenolic group obtained from the essential oils of oregano and thyme. These plants are being used as food flavoring spice and as fragrance ingredient in various cosmetic formulations. For the use of CRV as an efficient chemopreventive agent, different therapeutic interactions of CRV along with its targeted pathways and molecules, involved in the regulation of onset and progression of various types of solid carcinomas, need to be studied and explored thoroughly.
    Keywords:  anticancer; cancer; carvacrol; chemopreventive; solid carcinomas
    DOI:  https://doi.org/10.1111/jfbc.14010
  16. Front Pharmacol. 2021 ;12 731492
    The Adroitness of Andrographolide as a Natural Weapon Against Colorectal Cancer.
    Silpita Paul, Dia Roy, Subhadip Pati, Gaurisankar Sa.
      The conventional carcinoma treatment generally encompasses the employment of radiotherapy, chemotherapy, surgery or use of cytotoxic drugs. However, recent advances in pharmacological research have divulged the importance of traditional treatments in cancer. The aim of the present review is to provide an overview of the importance of one such medicinal herb of Chinese and Indian origin: Andrographis paniculate on colorectal cancer with special emphasis on its principal bioactive component andrographolide (AGP) and its underlying mechanisms of action. AGP has long been known to possess medicinal properties. Studies led by numerous groups of researchers shed light on its molecular mechanism of action. AGP has been shown to act in a multi-faceted manner in context of colorectal cancer by targeting matrix metalloproteinase-9, Toll-like receptor or NFκB signaling pathways. In this review, we highlighted the recent studies that show that AGP can act as an effective immunomodulator by harnessing effective anti-tumor immune response. Recent studies strongly recommend further research on this compound and its analogues, especially under in-vivo condition to assess its actual potential as a prospective and efficient candidate against colorectal cancer. The current review deals with the roles of this phytomedicine in context of colorectal cancer and briefly describes its perspectives to emerge as an essential anti-cancer drug candidate. Finally, we also point out the drawbacks and difficulties in administration of AGP and indicate the use of nano-formulations of this phytomedicine for better therapeutic efficacy.
    Keywords:  Andrographolide; Antitumor; Colorectal cancer; Phytochemical; immunomodulator
    DOI:  https://doi.org/10.3389/fphar.2021.731492
  17. J Food Biochem. 2021 Nov 14. e13986
    An updated review on pharmacological properties of neferine-A bisbenzylisoquinoline alkaloid from Nelumbo nucifera.
    Lohanathan Bharathi Priya, Chih-Yang Huang, Rouh-Mei Hu, Balamuralikrishnan Balasubramanian, Rathinasamy Baskaran.
      Phytochemicals have recently received a lot of recognition for their pharmacological activities such as anticancer, chemopreventive, and cardioprotective properties. In traditional Indian and Chinese medicine, parts of lotus (Nelumbo nucifera) such as lotus seeds, fruits, stamens, and leaves are used for treating various diseases. Neferine is a bisbenzylisoquinoline alkaloid, a major component from the seed embryos of N. nucifera. Neferine is effective in the treatment of high fevers and hyposomnia, as well as arrhythmia, platelet aggregation, occlusion, and obesity. Neferine has been found to have a variety of therapeutic effects such as anti-inflammatory, anti-oxidant, anti-hypertensive, anti-arrhythmic, anti-platelet, anti-thrombotic, anti-amnesic, and negative inotropic. Neferine also exhibited anti-anxiety effects, anti-cancerous, and chemosensitize to other anticancer drugs like doxorubicin, cisplatin, and taxol. Induction of apoptosis, autophagy, and cell cycle arrest are the key pathways that underlying the anticancer activity of neferine. Therefore, the present review summarizes the neferine biosynthesis, pharmacokinetics, and its effects in myocardium, cancer, chemosensitizing to cancer drug, central nervous system, diabetes, inflammation, and kidney diseases. PRACTICAL APPLICATIONS: Natural phytochemical is gaining medicinal importance for a variety of diseases like including cancer, neurodegenerative disorder, diabetes, and inflammation. Alkaloids and flavonoids, which are abundantly present in Nelumbo nucifera have many therapeutic applications. Neferine, a bisbenzylisoquinoline alkaloid from N. nucifera has many pharmacological properties. This present review was an attempt to compile an updated pharmacological action of neferine in different disease models in vitro and in vivo, as well as to summarize all the collective evidence on the therapeutic potential of neferine.
    Keywords:  anticancer; apoptosis; bisbenzylisoquinoline alkaloid; lotus; neferine
    DOI:  https://doi.org/10.1111/jfbc.13986
  18. J Food Biochem. 2021 Nov 19. e14005
    Diosgenin a steroidal compound: An emerging way to cancer management.
    Prajya Arya, Pradyuman Kumar.
      To endure respective research for cancer via common food ingredients has become more prominent with preferably minuscule toxicity. Spices are emerging as a new source of bioactive compounds which have the potential to cure cancer. Fenugreek is rich in diosgenin that has curative and preventive potency toward various cancers. Cancer is invading various cellular mechanisms by altering cellular receptors. Cancer falsifies healthy cells by altered cell receptors like p38, p53, mTOR, Akt, and PARP. Distinct stages of cancer development are triggered by various cellular mechanisms. Diosgenin helps in suppressing cancer mechanisms and induces programmed cell death. Diosgenin brought changes in treatment line of lung, breast, prostate, liver, and colon cancer. Apoptosis changes cytoplasmic different caspase pathways and triggers selected sequence for cancer cell line death. Cell death comprised of series of events carried out by metalloprotease caspase. The complex relationship among cancer, caspase, cell death, and cellular receptors is reviewed in this article in respect of diosgenin. The utilization of diosgenin in creating a bar for cancer, its triggering sites, and various ways to cause apoptosis of abnormal cells. This article focused on diosgenin, its role in the prevention of different cancer and cellular apoptosis throughout different pathways involved in complex interaction of bioactive compound-cellular mechanism cancer. PRACTICAL APPLICATIONS: The concept of curing diseases from daily routine food is quite old. Fenugreek is an excellent source of various bioactive compounds especially diosgenin. Diosgenin is steroidal sapogenin that cures various health issues including cancers. Cancer is one of the most life-threating disease which can affect any cell, tissue, and organ in living system. Diosgenin is proved to be beneficial in terms curing cancer of various types but majorly include lung, liver, colon breast, and prostate. Cancer cure with diosgenin is providing a new base to the pharmaceutical and medical researchers to commence new and more specific journey of diosgenin. Diosgenin could alter cellular pathways that modify cell mechanism in way toward treating cancer. Cell mechanism mainly affected by the interaction of cell signals and cell different receptors that cause triggered cell death. This review article focused over various cancer and diosgenin effect in controlling different cellular pathways which include cellular signaling and cell death mechanism.
    Keywords:  bioactive compound; cancer; cell death mechanism; diosgenin; suppressor protein
    DOI:  https://doi.org/10.1111/jfbc.14005
  19. Phytomedicine. 2021 Oct 19. pii: S0944-7113(21)00350-0. [Epub ahead of print] 153807
    Agrimoniin sensitizes pancreatic cancer to apoptosis through ROS-mediated energy metabolism dysfunction.
    Xiandong Zhu, Yan Zhang, Yongqiang Wang, Hewei Zhang, Xiaowu Wang, Hengjie Tang, Hongjian Huang, Zijun Zhou, Bicheng Chen, Linxiao Sun.
      BACKGROUND: Pancreatic cancer is a fatal tumor, which is one of the most common malignant tumors at present. Patients with pancreatic cancer also respond poorly to chemotherapy or radiation therapy and may be accompanied by serious adverse reactions. Therefore, to find an effective way to inhibit the initiation and progression of pancreatic cancer is important to improve the survival and development of patients. Agrimoniin, a polyphenol compounds isolated from Agrimonia pilosa ledeb, has antiviral, antimicrobial, and anticancer activities in vivo and in vitro. However, its molecular mechanism in pancreatic cancer remains to be determined.PURPOSE: We aimed to investigate the effect of agrimoniin in pancreatic cancer and its underlying mechanism in vivo and in vitro.
    METHODS: The proliferation was detected by colony formation, cell proliferation and toxicity, and real-time cell analysis techniques. The apoptosis was detected by flow cytometry and Western blot. Flow cytometry was used to measure the level of reactive oxygen species (ROS) and apoptosis. The level of intracellular ROS or mitochondrial membrane potential was measured with a DCFH-DA or JC-1 probe. Cell metabolism assays were analyzed and evaluated by using Agilent Seahorse Bioscience XF96 Extracellular Flux Analyzer. The target proteins were analyzed by Western blot. Subcutaneous cancer models in nude mice were established to evaluate the anticancer effects in vivo.
    RESULTS: Agrimoniin inhibited cell growth and promoted cell apoptosis by regulating cell metabolism in pancreatic cancer cells. Agrimoniin increased the ROS level in pancreatic cancer cells by suppressing Nrf2-dependent ROS scavenging system and disrupting normal mitochondrial membrane potential. We also found that agrimoniin significantly disrupted mitochondrial function and reduced the protein expression of mTOR/HIF-1α pathway and subsequently decreased oxygen consumption rate and extracellular acidification rate. Eventually, agrimoniin affected intracellular energy metabolism and induced apoptosis of pancreatic cancer cells.
    CONCLUSIONS: These findings reveal the novel function of agrimoniin in promoting apoptosis of pancreatic cancer cells through mediating energy metabolism dysfunction. Altogether, the potential new targets and their synergies discovered in this research are of great significance for cancer treatment and drug development.
    Keywords:  Agrimoniin; Energy metabolism; Pancreatic cancer; ROS
    DOI:  https://doi.org/10.1016/j.phymed.2021.153807
  20. Commun Biol. 2021 Nov 16. 4(1): 1289
    DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer.
    Ning Shen, Sovannarith Korm, Theodoros Karantanos, Dun Li, Xiaoyu Zhang, Eleni Ritou, Hanfei Xu, Andrew Lam, Justin English, Wei-Xing Zong, Ching-Ti Liu, Orian Shirihai, Hui Feng.
      Triple-negative breast cancer (TNBC) is traditionally considered a glycolytic tumor with a poor prognosis while lacking targeted therapies. Here we show that high expression of dihydrolipoamide S-succinyltransferase (DLST), a tricarboxylic acid (TCA) cycle enzyme, predicts poor overall and recurrence-free survival among TNBC patients. DLST depletion suppresses growth and induces death in subsets of human TNBC cell lines, which are capable of utilizing glutamine anaplerosis. Metabolomics profiling reveals significant changes in the TCA cycle and reactive oxygen species (ROS) related pathways for sensitive but not resistant TNBC cells. Consequently, DLST depletion in sensitive TNBC cells increases ROS levels while N-acetyl-L-cysteine partially rescues cell growth. Importantly, suppression of the TCA cycle through DLST depletion or CPI-613, a drug currently in clinical trials for treating other cancers, decreases the burden and invasion of these TNBC. Together, our data demonstrate differential TCA-cycle usage in TNBC and provide therapeutic implications for the DLST-dependent subsets.
    DOI:  https://doi.org/10.1038/s42003-021-02805-8
  21. Cancer Lett. 2021 Nov 16. pii: S0304-3835(21)00581-4. [Epub ahead of print]
    Jolkinolide B sensitizes bladder cancer to mTOR inhibitors via dual inhibition of Akt signaling and autophagy.
    Jun Sang, Lu Gan, Ming-Feng Zou, Zi-Jun Lin, Run-Zhu Fan, Jia-Luo Huang, Wei Li, Gui-Hua Tang, Sheng Yin.
      The monotherapy of mTOR inhibitors (mTORi) in cancer clinical practice has achieved limited success due to the concomitant activation of compensatory pathways, such as Akt signaling and cytoprotective autophagy. Thus, the combination of mTORi and the inhibitors of these pro-survival pathways has been considered a promising therapeutic strategy. Herein, we report the synergistic effects of a natural anti-cancer agent Jolkinolide B (JB) and mTORi (temsirolimus, rapamycin, and everolimus) for the effective treatment of bladder cancer. A mechanistic study revealed that JB induced a dual inhibition of Akt feedback activation and cytoprotective autophagy, potentiating the anti-proliferative efficacy of mTORi in both PTEN-deficient and cisplatin-resistant bladder cancer cells. Meanwhile, mTORi augmented the pro-apoptotic and pro-paraptotic effects of JB by reinforcing JB-activated endoplasmic reticulum stress and MAPK pathways. These synergistic mechanisms are related to cellular reactive oxygen species accumulation. Our study suggests that dual inhibition of Akt feedback activation and cytoprotective autophagy is an effective strategy in mTORi-based therapy, and JB + mTORi combination associated with multiple anti-cancer mechanisms and good tolerance in mouse models may serve as a promising treatment for bladder cancer.
    Keywords:  Apoptosis; Drug resistance; Natural diterpenoid; Paraptosis; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.canlet.2021.11.014
  22. Nat Metab. 2021 Nov;3(11): 1500-1511
    Methionine synthase is essential for cancer cell proliferation in physiological folate environments.
    Mark R Sullivan, Alicia M Darnell, Montana F Reilly, Tenzin Kunchok, Lena Joesch-Cohen, Daniel Rosenberg, Ahmed Ali, Matthew G Rees, Jennifer A Roth, Caroline A Lewis, Matthew G Vander Heiden.
      Folate metabolism can be an effective target for cancer treatment. However, standard cell culture conditions utilize folic acid, a non-physiological folate source for most tissues. We find that the enzyme that couples folate and methionine metabolic cycles, methionine synthase, is required for cancer cell proliferation and tumour growth when 5-methyl tetrahydrofolate (THF), the major folate found in circulation, is the extracellular folate source. In such physiological conditions, methionine synthase incorporates 5-methyl THF into the folate cycle to maintain intracellular levels of the folates needed for nucleotide production. 5-methyl THF can sustain intracellular folate metabolism in the absence of folic acid. Therefore, cells exposed to 5-methyl THF are more resistant to methotrexate, an antifolate drug that specifically blocks folic acid incorporation into the folate cycle. Together, these data argue that the environmental folate source has a profound effect on folate metabolism, determining how both folate cycle enzymes and antifolate drugs impact proliferation.
    DOI:  https://doi.org/10.1038/s42255-021-00486-5
  23. Biochem Pharmacol. 2021 Nov 11. pii: S0006-2952(21)00454-8. [Epub ahead of print] 114838
    Redox regulation by carotenoids: evidence and conflicts for their application in cancer.
    Gian Luigi Russo, Stefania Moccia, Maria Russo, Carmela Spagnuolo.
      Carotenoids have been constantly investigated since the early fifty for their chemical, biochemical and biological properties being presence in foods. Among the more than 1100 carotenoids synthesized by plants and microorganisms, approximately 50 are present in the human diet, and about 20 can be detected in human blood and tissues. Review articles that discuss the anticancer and cancer preventing activity of phytochemicals have often in common the difficulty to find a coherency between the results deriving from experimental studies and the controversial or weak clinical indications arising from epidemiological and interventional studies. In this scenario, the class of carotenoids does not represent an exception. In fact, according with World Cancer Research Fund, strong evidence exists that high-dose supplementation of β-carotene increases the risk of lung cancer, while for other types of cancer, the protective or harmful effects of food-containing carotenoids or carotenoid supplements have been considered limited, suggestive or unlikely. The analysis of the mechanistic evidence is complicated by the double nature of carotenoids being molecules acting either as antioxidant or pro-oxidant compounds. The present review analyzes the ambiguity and the unexpected results deriving from the epidemiological and interventional studies and discusses how the effects of carotenoids on cancer risk can be explained by understanding their capacity to modulate the cellular antioxidant response, depending on the concentration applied and the cellular metabolism. In the final part, a new global approach is proposed to study the contribution of carotenoids, but also of other phytochemicals, to disease prevention, including cancer.
    Keywords:  Carotenoids; antioxidant activity; cancer; lycopene; pro-oxidant activity; α-carotene; β-carotene
    DOI:  https://doi.org/10.1016/j.bcp.2021.114838
  24. Ann Transl Med. 2021 Oct;9(20): 1599
    A narrative review of mechanisms of ferroptosis in cancer: new challenges and opportunities.
    Mingyan Jiang, Ruolan Hu, Ruixin Yu, Yiwei Tang, Jinrong Li.
      Objective: This article reviews the specific mechanism of ferroptosis in cancer and introduces in detail the opportunities and challenges of ferroptosis-based cancer therapy, aiming to provide a new research direction for tumor therapy.Background: Ferroptosis is a newly discovered programmed non-apoptotic form of cell death. Involving changes in metabolic processes and the accumulation of peroxidation caused by factors such as drugs or genes which destruct the cell membrane structure, this kind of cell death has been linked with the pathological process of diseases such as tumors, neurological diseases, ischemia-reperfusion injury, kidney injury, and hemopathy. This kind of cell death can play a vital role in inhibiting tumorigenesis by eliminating the adaptive characteristics of malignant cells and removing cells that are unable to obtain key nutritional factors or are infected and damaged by environmental changes. The present focus of research on the regulation of ferroptosis-related diseases involves the use of small molecule compounds.
    Methods: We described the mechanism of ferroptosis and its related small molecules compounds, which involved in the regulatory mechanism, and analyzed the role and regulatory mechanism of ferroptosis in different tumors.
    Conclusions: This article reviewed the mechanism of ferroptosis and its role and mechanism in different tumors, and showed it can inhibit the occurrence and development of different tumors and may reduce the adverse effects of current treatment methods.
    Keywords:  Ferroptosis; cancer; mechanism of action
    DOI:  https://doi.org/10.21037/atm-21-4863
  25. Curr Drug Metab. 2021 Nov 17.
    How Antimalarials and Antineoplastic Drugs can Interact in Combination Therapies: a Perspective on the Role of PPT1 Enzyme.
    Diana Duarte, Nuno Vale.
      Antimalarial drugs from different classes have demonstrated anticancer effects in different types of cancer cells, but their complete mode of action in cancer remains unknown. Recently, several studies reported the important role of palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme, as the molecular target of chloroquine and its derivates in cancer. It was also found that PPT1 is overexpressed in different types of cancer, such as breast, colon, etc. Our group has found a synergistic interaction between antimalarial drugs, such as mefloquine, artesunate and chloroquine and antineoplastic drugs in breast cancer cells, but the mechanism of action was not determined. Here, we describe the importance of autophagy and lysosomal inhibitors in tumorigenesis and hypothesize that other antimalarial agents besides chloroquine could also interact with PPT1 and inhibit the mechanistic target of rapamycin (mTOR) signalling, an important pathway in cancer progression. We believe that PPT1 inhibition results in changes in the lysosomal metabolism that result in less accumulation of antineoplastic drugs in lysosomes, which increases the bioavailability of the antineoplastic agents. Taken together, these mechanisms help to explain the synergism of antimalarial and antineoplastic agents in cancer cells.
    Keywords:  Antimalarial drugs; Antineoplastic drugs; Autophagy; Drug combination.; PPT1; mTOR
    DOI:  https://doi.org/10.2174/1389200222666211118114057
  26. Acta Biomater. 2021 Nov 11. pii: S1742-7061(21)00750-9. [Epub ahead of print]
    Silk fibroin-capped metal-organic framework for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy.
    Honglian Yu, Yongcan Li, Zhiyu Zhang, Junjie Ren, Lei Zhang, Zhigang Xu, Yuejun Kang, Peng Xue.
      Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression. Therefore, synergistic effects arising from cellular redox imbalance together with other treatment modalities are worth further investigation. Herein, a metal-organic framework nanosystem (NMOF) based on coordination between Fe (III) and 4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) was synthesized through a one-pot method. After surface capping of silk fibroin (SF) to form NMOF@SF nanoparticles (NPs), this nanoplatform can serve as an eligible nanocarrier to deliver tirapazamine (TPZ), a hypoxia-activated precursor. As-developed NS@TPZ (NST) NPs remained inactive in the normal tissue, whereas became highly active upon endocytosis by tumor cells via glutathione (GSH)-mediated reduction of Fe (III) into Fe (II), further enabling Fe (II)-mediated chemodynamic therapy (CDT). Upon optical laser irradiation, TCPP-mediated photodynamic therapy (PDT) coordinated with CDT to aggravate intracellular oxidative stress. Thus, such reactive oxygen species accumulation and GSH deprivation contributed to a deleterious redox dyshomeostasis. On the other hand, local deoxygenation caused by PDT can increase the cytotoxicity of released TPZ, which significantly improved the integral therapeutic effectiveness relying on the combined redox balance disruption and bioreductive chemotherapy. More importantly, severe immunogenic cell death can be triggered by the combinatorial treatment modalities and the presence of SF, which facilitated an almost complete tumor eradication in vivo. Taken together, this paradigm provides an insightful strategy for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy, which can remarkably enhance antitumor efficacy with negligible adverse effects. STATEMENT OF SIGNIFICANCE: : Recently, silk fibroin (SF) has been demonstrated to be effective in activating antitumor immune system through polarization tumor-associated macrophages into M1 subtype. However, engineering SF into multifunctional nanocomposites is seldom reported for combination tumor therapy. In another aspect, disruption of redox homeostasis becomes increasingly attractive for tumor suppression with high clinical-relevance. Herein, we established a newfashioned NMOF nanosystem, named as NST, for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy. This platform takes advantages of Fe2+/Fe3+ coupled Fenton-like reaction and GSH depletion, as well as TCPP-mediated photosensitization for admirable redox unbalancing, which further initiates hypoxia-relevant toxin of TPZ for chemotherapy. Finally, combinatorial treatments and the presence of SF could trigger ICD for rendering a complete tumor eradication in vivo.
    Keywords:  metal-organic framework; silk fibroin; tirapazamine; tumor microenvironment; tumor therapy
    DOI:  https://doi.org/10.1016/j.actbio.2021.11.009
  27. Front Pharmacol. 2021 ;12 738914
    Role of Bioactive Constituents of Panax notoginseng in the Modulation of Tumorigenesis: A Potential Review for the Treatment of Cancer.
    Ming-Ming Tan, Min-Hua Chen, Fang Han, Jun-Wei Wang, Yue-Xing Tu.
      Cancer is a leading cause of death, affecting people in both developed and developing countries. It is a challenging disease due to its complicated pathophysiological mechanism. Many anti-cancer drugs are used to treat cancer and reduce mortality rates, but their toxicity limits their administration. Drugs made from natural products, which act as multi-targeted therapy, have the ability to target critical signaling proteins in different pathways. Natural compounds possess pharmacological activities such as anti-cancer activity, low toxicity, and minimum side effects. Panax notoginseng is a medicinal plant whose extracts and phytochemicals are used to treat cancer, cardiovascular disorders, blood stasis, easing inflammation, edema, and pain. P. notoginseng's secondary metabolites target cancer's dysregulated pathways, causing cancer cell death. In this review, we focused on several ginsenosides extracted from P. notoginseng that have been evaluated against various cancer cell lines, with the aim of cancer treatment. Furthermore, an in vivo investigation of these ginsenosides should be conducted to gain insight into the dysregulation of several pathways, followed by clinical trials for the potential and effective treatment of cancer.
    Keywords:  P notoginseng; anti-cancer drugs; multi-targeted; phytochemicals; secondary metabolites; signaling proteins
    DOI:  https://doi.org/10.3389/fphar.2021.738914
  28. Cancer Gene Ther. 2021 Nov 16.
    Decellularized normal and cancer tissues as tools for cancer research.
    E Gentilin, E D'Angelo, M Agostini, L Astolfi.
      Today it is widely accepted that molecular mechanisms triggering cancer initiate with a genetic modification. However, a genetic alteration providing the aberrant clone with a growing advantage over neighboring cells is not sufficient to develop cancer. Currently, tumors are considered a heterogeneous population of cells and an extracellular matrix (ECM) that make up a characteristic microenvironment. Interactions between tumor cells and cancer microenvironment define cancer progression and therapeutic response. To investigate and clarify the role of ECM in the regulation of cancer cell behavior and response to therapy, the decellularization of ECM, a widely used technique in tissue engineering, has been recently employed to develop 3D culture model of disease. In this review, we briefly explore the different components of healthy and pathological ECM and the methods to obtain and characterize the ECM from native bioptic tissue. Finally, we highlight the most relevant applications of ECM in translational cancer research strategies: decellularized ECM, ECM-hydrogel and 3D bioprinting.
    DOI:  https://doi.org/10.1038/s41417-021-00398-2
  29. J Oncol Pharm Pract. 2021 Nov 18. 10781552211056856
    Capecitabine-induced leukoencephalopathy in a patient with triple-negative breast cancer: A case report and review of the literature.
    Li Liu, Erika N Brown, Fadi I Abu-Shahin.
      INTRODUCTION: Capecitabine is an orally administered prodrug that converts preferentially to 5-fluorouracil within tumors, resulting in enhanced concentrations of 5-fluorouracil in tumor tissue. The use of capecitabine has shown efficacy in the metastatic setting for breast cancer, and more recently, efficacy as adjuvant therapy for triple-negative breast cancer (TNBC). Capecitabine has been shown to be well tolerated with minimal side effects, but the incidence of leukoencephalopathy is rare with a risk of less than one percent.CASE REPORT: We report on a 34-year-old female patient with left TNBC, moderately differentiated, stage IIB that experienced symptoms of neurotoxicity following initiation of adjuvant chemotherapy with capecitabine.
    MANAGEMENT AND OUTCOME: Naranjo Algorithm Assessment score of nine indicated patient had drug-induced leukoencephalopathy leading to discontinuation of capecitabine and resolution of the neurotoxicity symptoms.
    DISCUSSION: Early detection of capecitabine-induced neurotoxicity by magnetic resonance imaging is crucial as symptoms may be reversible to the condition that capecitabine is immediately discontinued.
    Keywords:  5-fluorouracil; Triple-negative breast cancer; capecitabine; drug-induced leukoencephalopathy; neurotoxicity
    DOI:  https://doi.org/10.1177/10781552211056856
  30. J Med Chem. 2021 Nov 16.
    NSAIDs: Old Acquaintance in the Pipeline for Cancer Treatment and Prevention─Structural Modulation, Mechanisms of Action, and Bright Future.
    Sandra Ramos-Inza, Ana Carolina Ruberte, Carmen Sanmartín, Arun K Sharma, Daniel Plano.
      The limitations of current chemotherapeutic drugs are still a major issue in cancer treatment. Thus, targeted multimodal therapeutic approaches need to be strategically developed to successfully control tumor growth and prevent metastatic burden. Inflammation has long been recognized as a hallmark of cancer and plays a key role in the tumorigenesis and progression of the disease. Several epidemiological, clinical, and preclinical studies have shown that traditional nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit anticancer activities. This Perspective reports the most recent outcomes for the treatment and prevention of different types of cancers for several NSAIDs alone or in combination with current chemotherapeutic drugs. Furthermore, an extensive review of the most promising structural modifications is reported, such as phospho, H2S, and NO releasing-, selenium-, metal complex-, and natural product-NSAIDs, among others. We also provide a perspective about the new strategies used to obtain more efficient NSAID- or NSAID derivative- formulations for targeted delivery.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c01460
  31. Nanomedicine. 2021 Nov 11. pii: S1549-9634(21)00135-0. [Epub ahead of print] 102492
    Harnessing the Combined Potential of Cancer Immunotherapy and Nanomedicine: A New Paradigm in Cancer Treatment.
    Cherylette Anne Alexander, Yi Yan Yang.
      Cancer immunotherapy has recently emerged as a rising star due to its ability to activate patients' immune systems to fight tumors and prevent relapse. Conversely, the interest in cancer nanomedicine has seemingly waned due to its lackluster clinical translation. Despite being hailed as a game-changer in oncology, cancer immunotherapy still faces numerous challenges. Combining both entities together, has thus been one amongst several solutions proposed to circumvent these challenges. This solution has since gained traction and has also led to a renaissance of cancer nanomedicine. While most combinations are currently experimental at best, some have progressed on to clinical trials. This review thus seeks to examine the advantages and disadvantages of integrating both modalities as a cancer treatment. The opportunities, challenges and future directions of this emerging field will also be explored with the hope that such a combination will lead to a paradigm shift in cancer treatments.
    DOI:  https://doi.org/10.1016/j.nano.2021.102492
  32. Curr Med Chem. 2021 Nov 16.
    Copper complexes as antitumor agents: in vitro and in vivo evidences.
    Lucia M Balsa, Enrique J Baran, Ignacio E León.
      Copper is an essential element for most aerobic organisms, with an important function as a structural and catalytic cofactor, and in consequence, it is implicated in several biological actions. The relevant aspects of chemistry and biochemistry and the importance of copper compounds in medicine give us a comprehensive knowledge of the multifaceted applications of copper in physiology and physiopathology. In this review, we present an outline of the chemistry and the antitumor properties of copper complexes on breast, colon, and lung cancer cells focus on the role of copper in cancer, the relationship between structure-activity, molecular targets, and the study of the mechanism of action involved in its anticancer activity. This overview is expected to contribute to understanding the design, synthesis, uses of copper complexes as antitumor agents in the most common cancers.
    Keywords:  Cancer; Copper; Mechanism of action; SAR; cisplatin; tumors
    DOI:  https://doi.org/10.2174/0929867328666211117094550
  33. Crit Rev Food Sci Nutr. 2021 Nov 16. 1-29
    Targeting long non coding RNA by natural products: Implications for cancer therapy.
    Mina Homayoonfal, Zatollah Asemi, Bahman Yousefi.
      In spite of achieving substantial progress in its therapeutic strategies, cancer-associated prevalence and mortality are persistently rising globally. However, most malignant cancers either cannot be adequately diagnosed at the primary phase or resist against multiple treatments such as chemotherapy, surgery, radiotherapy as well as targeting therapy. In recent decades, overwhelming evidences have provided more convincing words on the undeniable roles of long non-coding RNAs (lncRNAs) in incidence and development of various cancer types. Recently, phytochemical and nutraceutical compounds have received a great deal of attention due to their inhibitory and stimulatory effects on oncogenic and tumor suppressor lncRNAs respectively that finally may lead to attenuate various processes of cancer cells such as growth, proliferation, metastasis and invasion. Therefore, application of phytochemicals with anticancer characteristics can be considered as an innovative approach for treating cancer and increasing the sensitivity of cancer cells to standard prevailing therapies. The purpose of this review was to investigate the effect of various phytochemicals on regulation of lncRNAs in different human cancer and evaluate their capabilities for cancer treatment and prevention.
    Keywords:  Apoptosis; cancer therapy; long non-coding RNA (lncRNA); metastasis; natural product; phytochemical; proliferation
    DOI:  https://doi.org/10.1080/10408398.2021.2001785
  34. Cancer Med. 2021 Nov 18.
    Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models.
    Enrica Balza, Sebastiano Carlone, Sonia Carta, Patrizia Piccioli, Vanessa Cossu, Cecilia Marini, Gianmario Sambuceti, Anna Rubartelli, Patrizia Castellani.
      Triple negative breast cancers (TNBCs) are very aggressive and have a poor prognosis due to lack of efficacious therapies. The only effective treatment is chemotherapy that however is frequently hindered by the occurrence of drug resistance. We approached this problem in vitro and in vivo on a triple negative and a hormone sensitive breast cancer cell lines: 4T1 and TS/A. A main defense mechanism of tumors is the extrusion of intracellular protons derived from the metabolic shift to glycolysis, and necessary to maintain an intracellular pH compatible with life. The resulting acidic extracellular milieu bursts the malignant behavior of tumors and impairs chemotherapy. Therefore, we investigated the efficacy of combined therapies that associate cisplatin (Cis) with proton exchanger inhibitors, such as esomeprazole (ESO) and 5-(N-ethyl-N-isopropyl)amiloride (EIPA). Our results demonstrate that in the 4T1 triple negative model the combined therapy Cis plus EIPA is significantly more effective than the other treatments. Instead, in the TS/A tumor the best therapeutic result is obtained with ESO alone. Remarkably, in both 4T1 and TS/A tumors these treatments correlate with increase of CD8+  T lymphocytes and dendritic cells, and a dramatic reduction of M2 macrophages and other suppressor myeloid cells (MDSC) in the tumor infiltrates.
    Keywords:  breast cancer; cisplatin; combo therapies; immune response; proton exchanger inhibitors
    DOI:  https://doi.org/10.1002/cam4.4371
  35. Bioengineered. 2021 Nov 16.
    Size-dependent chemosensitization of doxorubicin-loaded polymeric nanoparticles for malignant glioma chemotherapy.
    Meng Gao, Yue Chen, Chenghu Wu.
      Chemotherapy is a traditional treatment method in clinical cancer treatment. However, it is limited due to the large toxic side effects of chemotherapeutics. Nanomedicines have shown great potential in the application of tumor therapy. The size of nanoparticles as a crucial factor in the enhanced permeability and retention (EPR) effect can be regulated for the enhanced chemotherapy. Therefore, we believe that regulation of nanoparticle size can be used as an effective sensitizer to enhance the therapeutic effect of chemotherapy drugs on tumors. Here, we prepared several nanoparticles of different hydrodynamic diameters commonly found in nanomedical applications by the diblock copolymer of methoxy polyethylene glycol- poly (ϵ-caprolactone) (mPEG-PCL). The blood circulation effect and organ distribution in blood were detected by fluorescence labeled nanoparticles. We found that the small-sized nanoparticles exhibited much longer blood circulation time than the large-sized nanoparticles in vivo, and thus the nanoparticle concentration in the tumor tissue was relatively high. Systematic injection of the doxorubicin (DOX) loaded nanoparticles can effectively inhibit tumor growth. Compared to the free drug, tumor cells were much more sensitive to DOX loaded nanoparticles of small size. Our nano-drug delivery system has been proven to be safe and non-toxic in vivo and was suitable for use as a sensitizer in clinical oncology chemotherapy.
    Keywords:  Chemosensitization; Doxorubicin-loaded nanoparticles; Malignant glioma; Size-dependent; Tumor chemotherapy
    DOI:  https://doi.org/10.1080/21655979.2021.2006568
  36. Adv Mater. 2021 Nov 15. e2106773
    Engineering Electronic Band Structure of Binary Thermoelectric Nanocatalysts for Augmented Pyrocatalytic Tumor Nanotherapy.
    Yachao Wang, Xinyue Dai, Caihong Dong, Weitao Guo, Ziwei Xu, Ruifang Zhang, Huijing Xiang, Yu Chen.
      Photothermal therapy (PTT) has emerged as a distinct therapeutic modality owing to its non-invasiveness and spatiotemporal selectivity. However, the heat-shock proteins (HSPs) endow tumor cells with resistance to heat-induced apoptosis, severely lowering the therapeutic efficacy of PTT. In this study, we developed a high-performance pyroelectric nanocatalyst, Bi13 S18 I2 nanorods (Nrs), with prominent pyroelectric conversion and photothermal conversion performance for augmented pyrocatalytic tumor nanotherapy. Canonical binary compounds were reconstructed by inserting a third biocompatible agent, thus facilitating the formation of Bi13 S18 I2 Nrs with enhanced pyrocatalytic conversion efficiency. Under 808 nm laser irradiation, Bi13 S18 I2 Nrs induced a conspicuous temperature elevation for photonic hyperthermia. In particular, Bi13 S18 I2 Nrs harvested pyrocatalytic energy from the heating and cooling alterations to produce abundant reactive oxygen species (ROS), which resulted in the depletion of HSPs and hence the reduction of thermo-resistance of tumor cells, thereby significantly augmenting the therapeutic efficacy of photothermal tumor hyperthermia. By synergizing the pyroelectric dynamic therapy with PTT, tumor suppression with a significant tumor inhibition rate of 97.2% was achieved after intravenous administration of Bi13 S18 I2 Nrs and subsequent exposure to an 808 nm laser. This work opens an avenue for the design of high-performance pyroelectric nanocatalysts by reconstructing canonical binary compounds for therapeutic applications in biocatalytic nanomedicine. This article is protected by copyright. All rights reserved.
    Keywords:  Bi13S18I2 nanorods; Pyroelectric dynamic therapy; ROS generation; nanomedicine; photonic hyperthermia
    DOI:  https://doi.org/10.1002/adma.202106773
  37. Front Oncol. 2021 ;11 758549
    Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.
    Keiichiro Okuda, Atsushi Umemura, Seita Kataoka, Kota Yano, Aya Takahashi, Shinya Okishio, Hiroyoshi Taketani, Yuya Seko, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Hayato Nakagawa, Yu Liu, Yasuhide Mitsumoto, Yoshihiro Kanbara, Toshihide Shima, Takeshi Okanoue, Yoshito Itoh.
      Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.
    Keywords:  L-asparaginase; asparagine; asparagine synthetase; glutamine; glutamine synthetase; lenvatinib; liver cancer; oxidative stress
    DOI:  https://doi.org/10.3389/fonc.2021.758549
  38. BMC Genomics. 2021 Nov 19. 22(1): 840
    Systematic analysis of the lysine malonylome in Sanghuangporus sanghuang.
    Tong Wang, Guangyuan Wang, Guoli Zhang, Ranran Hou, Liwei Zhou, Xuemei Tian.
      BACKGROUND: Sanghuangporus sanghuang is a well-known traditional medicinal mushroom associated with mulberry. Despite the properties of this mushroom being known for many years, the regulatory mechanisms of bioactive compound biosynthesis in this medicinal mushroom are still unclear. Lysine malonylation is a posttranslational modification that has many critical functions in various aspects of cell metabolism. However, at present we do not know its role in S. sanghuang. In this study, a global investigation of the lysine malonylome in S. sanghuang was therefore carried out.RESULTS: In total, 714 malonyl modification sites were matched to 255 different proteins. The analysis indicated that malonyl modifications were involved in a wide range of cellular functions and displayed a distinct subcellular localization. Bioinformatics analysis indicated that malonylated proteins were engaged in different metabolic pathways, including glyoxylate and dicarboxylate metabolism, glycolysis/gluconeogenesis, and the tricarboxylic acid (TCA) cycle. Notably, a total of 26 enzymes related to triterpene and polysaccharide biosynthesis were found to be malonylated, indicating an indispensable role of lysine malonylation in bioactive compound biosynthesis in S. sanghuang.
    CONCLUSIONS: These findings suggest that malonylation is associated with many metabolic pathways, particularly the metabolism of the bioactive compounds triterpene and polysaccharide. This paper represents the first comprehensive survey of malonylation in S. sanghuang and provides important data for further study on the physiological function of lysine malonylation in S. sanghuang and other medicinal mushrooms.
    Keywords:  Malonylation; Malonylproteome; Posttranslational modification (PTM); Sanghuangporus sanghuang
    DOI:  https://doi.org/10.1186/s12864-021-08120-0
  39. Sovrem Tekhnologii Med. 2021 ;12(4): 91-102
    Modern Approaches to Testing Drug Sensitivity of Patients' Tumors (Review).
    I N Druzhkova, M V Shirmanova, D S Kuznetsova, М М Lukina, Е V Zagaynova.
      Drug therapy is still one of the basic techniques used to treat cancers of different etiology. However, tumor resistance to drugs is a pressing problem limiting drug treatment efficacy. It is obvious for both modern fundamental and clinical oncology that there is the need for an individual approach to treating cancer taking into account the biological properties of a tumor when prescribing chemo- and targeted therapy. One of the promising strategies is to increase the antitumor therapy efficacy by developing predictive tests, which enable to evaluate the sensitivity of a particular tumor to a specific drug or a drug combination before the treatment initiation and, thus, make individual therapy selection possible. The present review considers the main approaches to drug sensitivity assessment of patients' tumors: molecular genetic profiling of tumor cells, and direct efficiency testing of the drugs on tumor cells isolated from surgical or biopsy material. There were analyzed the key directions in research and clinical studies such as: the search for predictive molecular markers, the development of methods to maintain tumor cells or tissue sections viable, i.e. in a condition maximum close to their physiological state, the development of high throughput systems to assess therapy efficiency. Special attention was given to a patient-centered approach to drug therapy in colorectal cancer.
    Keywords:  cancer treatment selection; drug testing in vitro.; individualized cancer therapy; medical oncology; molecular genetic tumor testing
    DOI:  https://doi.org/10.17691/stm2020.12.4.11
  40. J Egypt Natl Canc Inst. 2021 Nov 15. 33(1): 34
    Implications of photodynamic cancer therapy: an overview of PDT mechanisms basically and practically.
    Nafiseh Sobhani, Ali Akbar Samadani.
      BACKGROUND: Tumor eradication is one of the most important challengeable categories in oncological studies. In this account, besides the molecular genetics methods including cell therapy, gene therapy, immunotherapy, and general cancer therapy procedures like surgery, radiotherapy, and chemotherapy, photodynamic adjuvant therapy is of great importance. Photodynamic therapy (PDT) as a relatively noninvasive therapeutic method utilizes the irradiation of an appropriate wavelength which is absorbed by a photosensitizing agent in the presence of oxygen. In this procedure, a series of events lead to the direct death of malignant cells such as damage to the microvasculature and also the induction of a local inflammatory function. PDT has participated with other treatment modalities especially in the early stage of malignant tumors and has resulted in decreasing morbidity besides improving survival rate and quality of life. High spatial resolution of PDT has attracted considerable attention in the field of image-guided photodynamic therapy combined with chemotherapy of multidrug resistance cancers. Although PDT outcomes vary across the different tumor types, minimal natural tissue toxicity, minor systemic effects, significant reduction in long-term disease, lack of innate or acquired resistance mechanisms, and excellent cosmetic effects, as well as limb function, make it a valuable treatment option for combination therapies.SHORT CONCLUSION: In this review article, we tried to discuss the potential of PDT in the treatment of some dermatologic and solid tumors, particularly all its important mechanisms.
    Keywords:  Cancerous tissues and cells; Mechanisms; Oncological studies; Photodynamic cancer therapy
    DOI:  https://doi.org/10.1186/s43046-021-00093-1
  41. J Vis Exp. 2021 Nov 01.
    Generation of an Orthotopic Xenograft of Pancreatic Cancer Cells by Ultrasound-Guided Injection.
    Tiziano Lottini, Matteo Buonamici, Claudia Duranti, Annarosa Arcangeli.
      Pancreatic cancer (PCa) represents one of the deadliest cancer types worldwide. The reasons for PCa malignancy mainly rely on its intrinsic malignant behavior and high resistance to therapeutic treatments. Indeed, despite many efforts, both standard chemotherapy and innovative target therapies have substantially failed when moved from preclinical evaluation to the clinical setting. In this scenario, the development of preclinical mouse models better mimicking in vivo characteristics of PCa is urgently needed to test newly developed drugs. The present protocol describes a method to generate a mouse model of PCa, represented by an orthotopic xenograft obtained by ultrasound-guided injection of human pancreatic tumor cells. Using such a reliable and minimally invasive protocol, we also provide evidence of in vivo engraftment and development of tumor masses, which can be monitored by ultrasound (US) imaging. A noteworthy aspect of the PCa model described here is the slow development of the tumor masses over time, which allows precise identification of the starting point for pharmacological treatments and better monitoring of the effects of therapeutic interventions. Moreover, the technique described here is an example of implementation of the 3Rs principles since it minimizes pain and suffering and directly improves the welfare of animals in research.
    DOI:  https://doi.org/10.3791/63123
  42. Anticancer Agents Med Chem. 2021 Oct 15.
    Exploring phytochemicals from Himalayan medicinal plants as novel therapeutic agents.
    Nidhi Saini, Viney Lather, Suresh Kumar Gahlawat.
      Over-prescription of medicines leads to some crucial health issues like resistance, non-specificity, etc. Therefore, a human consumes various natural foods, therapeutics, and nutritional supplements to combat this problem. Various therapeutic properties of secondary metabolites such as anticancer, anti-inflammatory, and antibacterial properties are important in drug discovery and medicinal application. These natural products has replaced synthetic materials, resulting in a great deal of sustainability, rational use and preservation of biodiversity. This review described the potential therapeutic applications of secondary plant metabolites found in Himalayan Indian plants. The database contains 45 plants to treat various diseases such as cancer, inflammation, and microbial infections. Besides authorized ITIS names, it includes Hindi names, family names, and active constituents. The most important information about the molecules can be found in the hyperlinks for the active constituents. It includes structures (two-dimensional and three-dimensional), names and identifiers, chemical and physical properties, spectral information, biochemistry, literature and patents. The review also references various phytochemicals responsible for preventing COVID-19. Despite several challenges in manufacturing natural products, researchers may conduct research to produce successful medicines with few side effects.
    Keywords:  Natural products; anti-tumoral; complementary medicine; drug discovery; herbal drug; plant-derived drugs; secondary metabolites
    DOI:  https://doi.org/10.2174/1871520621666211015141020
  43. Prog Mol Biol Transl Sci. 2021 ;pii: S1877-1173(21)00096-X. [Epub ahead of print]185 45-73
    AIE material for photodynamic therapy.
    Vishal Saini, V Venkatesh.
      Photodynamic therapy (PDT) is emerging as an excellent strategy to treat different types of cancers. The advantages of using PDT over other cancer treatment modalities are owing to its non-invasive nature, spatiotemporal precession, controllable photoactivity, and least side effects. The photosensitization ability of traditional photosensitizers (PSs) are severely curtailed by aggregation-induced quenching (ACQ). On the contrary, aggregation induced emission (AIE) molecules/fluorogens (AIEgens) show enhanced fluorescence emission and high reactive oxygen species (ROS)/singlet oxygen (1O2) production capability in the aggregated state. These unique characteristics of AIEgens make them potential AIE-PSs for fluorescence/luminescence image-guided combination PDT. In this chapter, we discussed the strategies that are developed to synthesize small molecule-based AIE-PSs, metal complex-based AIE-PSs, and AIE-PSs with two-photon absorbance (TPA) properties, polymer-based AIE-PSs, and nanoparticles based AIE-PSs for PDT. We have also discussed the rational design of targeting peptide conjugated AIE-PSs to selective target cancer cells over normal cells. Furthermore, recent findings on nanoparticle-based combination AIE-PSs are also discussed, where the combination AIE-PSs show synergistically improved anticancer activity and overcome the drug resistance. Finally, we shed light on the recent development, ongoing challenges, and future directions for designing better AIE-PS for PDT.
    Keywords:  AIE-PS nanoparticles; Aggregation-induced emission fluorogens; Aggregation-induced emission photosensitizer; Combination therapy; Fluorescence; Photodynamic therapy; Polymer based AIE-PS; Prodrug strategy; Reactive oxygen species; Singlet oxygen; Targeted AIE-PS; Two-photon absorbance
    DOI:  https://doi.org/10.1016/bs.pmbts.2021.06.010
  44. Drug Discov Today. 2021 Nov 12. pii: S1359-6446(21)00490-6. [Epub ahead of print]
    An updated review of folate-functionalized nanocarriers: a promising ligand in cancer.
    Pedram Ebrahimnejad, Arezoo Sodagar Taleghani, Kofi Asare-Addo, Ali Nokhodchi.
      The uncontrolled release of drugs in conventional drug delivery systems has led to the introduction of new nanotechnology-based drug delivery systems and the use of targeted nanocarriers for cancer treatment. These targeted nanocarriers, which consist of intelligent nanoparticles modified with targeting ligands, can deliver drugs to specified locations at the right time and reduce drug doses to prevent side effects. Folate is a suitable targeting ligand for folate receptors overexpressed on cancer cells and has shown promising results in the diagnosis and treatment of cancer. In this review, we highlight the latest developments on the use of folate-conjugated nanoparticles in cancer diagnosis and treatment. Moreover, the toxicity, biocompatibility and efficacy of these nanocarriers are discussed.
    Keywords:  Folic acid; cancer therapy; diagnosis; nanoparticles; targeted delivery
    DOI:  https://doi.org/10.1016/j.drudis.2021.11.011
  45. Drug Discov Today. 2021 Nov 11. pii: S1359-6446(21)00489-X. [Epub ahead of print]
    Therapeutic potential of curcumin in endometrial disorders: Current status and future perspectives.
    Apoorva Singh, Sanjukta Dasgupta, Anindita Bhattacharya, Gayatri Mukherjee, Koel Chaudhury.
      Endometrial disorders collectively encompass a broad spectrum of pathologies, including but not limited to endometriosis, endometrial cancer and endometritis. The current therapeutic management of these diseases is associated with several limitations. This has prompted interest in the use of plant-based bioactive compounds as alternative strategies to achieve high therapeutic efficacy and avoid adverse effects. In this context, curcumin, a polyphenol abundantly present in turmeric, is gaining increasing attention for its therapeutic potential to restore homeostasis in endometrial dysfunctionality. We comprehensively review the multifaceted role of curcumin, discussing mechanistic insights in various endometrial pathologies. We also provide an in-depth analysis of the concerns and challenges associated with the role of curcumin in endometrial research and outline a road map for future investigations.
    Keywords:  Curcumin; Endometrial cancer; Endometrial disorders; Endometriosis; Endometritis; Reproductive outcomes
    DOI:  https://doi.org/10.1016/j.drudis.2021.11.010
  46. Front Chem. 2021 ;9 763057
    Enzyme-Responsive Materials as Carriers for Improving Photodynamic Therapy.
    Houhe Liu, Fanwen Yang, Wenjie Chen, Teng Gong, Yi Zhou, Xiaoyan Dai, Wingnang Leung, Chuanshan Xu.
      Photodynamic therapy (PDT) is a mini-invasive therapy on malignancies via reactive oxygen species (ROS) induced by photosenitizer (PS) upon light irradiation. However, poor target of PS to tumor limits the clinical application of PDT. Compared with normal tissues, tumor tissues have a unique enzymatic environment. The unique enzymatic environment in tumor tissues has been widely used as a target for developing smart materials to improve the targetability of drugs to tumor. Enzyme-responsive materials (ERM) as a smart material can respond to the enzymes in tumor tissues to specifically deliver drugs. In PDT, ERM was designed to react with the enzymes highly expressed in tumor tissues to deliver PS in the target site to prevent therapeutic effects and avoid its side-effects. In the present paper, we will review the application of ERM in PDT and discuss the challenges of ERM as carriers to deliver PS for further boosting the development of PDT in the management of malignancies.
    Keywords:  carrier; enzyme-responsive materials; photodynamic therapy; photosensitizer; smart materials
    DOI:  https://doi.org/10.3389/fchem.2021.763057
  47. Homeopathy. 2021 Nov 17.
    Can Nanoparticles in Homeopathic Remedies Enhance Phototherapy of Cancer? A Hypothetical Model.
    Ayesha Loonat, Janice Pellow, Heidi Abrahamse, Rahul Chandran.
      The continuous rise in cancer incidence places a massive burden on the health sector to increase efforts in the fight against cancer. As a holistic complementary medicine modality, homeopathy has the potential to assist in the supportive and palliative treatment of cancer patients. Recent empirical studies demonstrate the presence of silica and original source nanoparticles in ultra-high dilutions of several homeopathic medicines. Recent studies have also demonstrated the efficacy of phototherapy in inducing the ablation of cancer cells through laser-activated nanoparticle photosensitizers. A new hypothetical research model is presented herein, in an attempt to investigate and compare the phototherapeutic effects of homeopathic source nanoparticles with photosensitizing nanoparticle agents that have previously been tested.
    DOI:  https://doi.org/10.1055/s-0041-1735581
  48. Biomed Pharmacother. 2021 Nov 16. pii: S0753-3322(21)01183-5. [Epub ahead of print]145 112397
    Anticancer activity of oleanolic acid and its derivatives: Recent advances in evidence, target profiling and mechanisms of action.
    Zhong-Yuan Tang, Yang Li, Yu-Ting Tang, Xiao-Dong Ma, Ze-Yao Tang.
      Oleanolic acid (OA, 3 β - hydroxyoleanolic acid-12-en-28-oic acid) is a pentacyclic triterpenoid present in many plants. As a new framework for development of semi synthetic triterpenoids, OA is of great significance in the discovery of anticancer drugs. Some of these derivatives, such as CDDO (2-cyano-3,12-dioxooleana-1, 9 (11)-dien-28-oic acid) have been verified in clinical trials, while other derivatives studied previously, such as SZC014, SZC015 and SZC017 (OA derivatives respectively), are also candidate drugs for cancer treatment. This paper reviews the preclinical studies, literature evidence, target analysis and anticancer mechanism of OA and its derivatives. The mechanism of action of its derivatives mainly includes anti-cancer cell proliferation, inducing tumor cell apoptosis, inducing autophagy, regulating cell cycle regulatory proteins, inhibiting vascular endothelial growth, anti angiogenesis, inhibiting tumor cell migration and invasion. In recent years, the molecular mechanism of OA and its derivatives has been elucidated. These effects seem to be mediated by the alterations in a variety of signaling pathways induced by OA and its derivatives. In conclusion, OA and its derivatives are considered as important candidate drugs for the treatment of cancer, indicating that OA and its derivatives have the potential to be used as anticancer drugs in practice.
    Keywords:  Angiogenesis; Apoptotic pathways; Derivatives; Metastasis; Oleanolic acid; Systematic -analysis review
    DOI:  https://doi.org/10.1016/j.biopha.2021.112397
  49. Front Nutr. 2021 ;8 744398
    Can Ketogenic Diet Improve Alzheimer's Disease? Association With Anxiety, Depression, and Glutamate System.
    Jose Enrique de la Rubia Ortí, David Fernández, Félix Platero, María Pilar García-Pardo.
      Background: Alzheimer's disease is the most common neurodegenerative disorder in our society, mainly characterized by loss of cognitive function. However, other symptoms such as anxiety and depression have been described in patients. The process is mediated by alterations in the synaptic and extrasynaptic activity of the neurotransmitter glutamate, which are linked to a hypometabolism of glucose as the main source of brain energy. In that respect, Ketogenic diet (KD) has been proposed as a non-pharmacological treatment serving as an alternative energy source to the neurons increasing the fat percentage and reducing the carbohydrates percentage, showing promising results to improve the cognitive symptoms associated with different neurodegenerative disorders, including AD. However, the association of this type of diet with emotional symptoms and the modulation of glutamate neurotransmission systems after this dietary reduction of carbohydrates are unknown. Objective: The aim of this short review is to provide update studies and discuss about the relationship between KD, anxiety, depression, and glutamate activity in AD patients. Discussion: The main results suggest that the KD is an alternative energy source for neurons in AD with positive consequences for the brain at different levels such as epigenetic, metabolic and signaling, and that the substitution of carbohydrates for fats is also associated with emotional symptoms and glutamate activity in AD.
    Keywords:  Alzheimer's disease; anxiety; depression; glutamate; ketogenic diets
    DOI:  https://doi.org/10.3389/fnut.2021.744398
  50. Chem Biol Interact. 2021 Nov 11. pii: S0009-2797(21)00383-5. [Epub ahead of print]351 109745
    Promises of phytochemical based nano drug delivery systems in the management of cancer.
    Parveen Kumar, Nishant Yadav, Benu Chaudhary, Vivek Jain, Vishal M Balaramnavar, Khalid Saad Alharbi, Sattam Khulaif Alenezi, Waleed Hassan Al-Malki, Mohammed M Ghoneim, Sultan Alshehri, Syed Sarim Imam, Madan Mohan Gupta.
      Cancer is the leading cause of human disease and death worldwide, accounting for 7.6 million deaths per year and projected to reach 13.1 million by 2030. Many phytochemicals included in traditional medicine have been utilized in the management of cancer. Conventional chemotherapy is generally known to be the most effective treatment of metastatic cancer but these cancerous cells might grow resistant to numerous anticancer drugs over time that resulting in treatment failure. This review tried to portray the advancement in the anticancer and chemopreventive effects of several phytochemicals and some of its members encapsulated in the nano-based delivery system of the drug. It comprises the issue associated with limited use of each phytoconstituents in human cancer treatment are discussed, and the benefits of entrapment into nanocarriers are evaluated in terms of drug loading efficiency, nanocarrier size, release profile of the drug, and in vitro and/or in vivo research and treatment testing, such as cytotoxicity assays and cell inhibition/viability.
    Keywords:  Cancer; Chemopreventive; Drug delivery; Nanocarrier; Phytochemical
    DOI:  https://doi.org/10.1016/j.cbi.2021.109745
  51. Phytomedicine. 2021 Oct 30. pii: S0944-7113(21)00371-8. [Epub ahead of print]94 153830
    Nanoscale delivery of phytochemicals targeting CRISPR/Cas9 for cancer therapy.
    Yaseen Hussain, Haroon Khan, Imad Ahmad, Thomas Efferth, Waqas Alam.
      BACKGROUND: With growing global prevalence, cancer is a major cause of disease-related deaths. The understanding of the fundamental tumor pathology has contributed to the development of agents targeting oncogenic signaling pathways. Although these agents have increased survival for defined cancers, the therapeutic choices are still limited due to the development of drug resistance. CRISPR/Cas9 is a powerful new technology in cancer therapy by facilitating the identification of novel treatment targets and development of cell-based treatment strategies.PURPOSE: We focused on applications of the CRISPR/Cas9 system in cancer therapy and discuss nanoscale delivery of cytotoxic phytochemical targeting the CRISPR/Cas9 system.
    RESULTS: Genome engineering has been significantly accelerated by the advancement of the CRISPR/Cas9 technique. Phytochemicals play a key role in treating cancer by targeting various mechanisms and pathways.
    CONCLUSIONS: The use of CRISPR/Cas9 for nanoscale delivery of phytochemicals opens new avenues in cancer therapy. One of the main obstacles in the clinical application of CRISPR/Cas9 is safe and efficient delivery. As viral delivery methods have certain drawbacks, there is an urgent need to develop non-viral delivery systems for therapeutic applications.
    Keywords:  CRISPR/Cas9; Genome editing; Nanotechnology; Phytochemicals
    DOI:  https://doi.org/10.1016/j.phymed.2021.153830
  52. Bioorg Med Chem. 2021 Nov 10. pii: S0968-0896(21)00501-0. [Epub ahead of print]51 116493
    Carbon nanomaterials as emerging nanotherapeutic platforms to tackle the rising tide of cancer - A review.
    Ahmad Reza Bagheri, Nahal Aramesh, Muhammad Bilal, Jiafu Xiao, Hae-Won Kim, Bing Yan.
      Cancer has become one of the main reasons for human death in recent years. Around 18 million new cancer cases and approximately 9.6 million deaths from cancer reported in 2018, and the annual number of cancer cases will have increased to 22 million in the next two decades. These alarming facts have rekindled researchers' attention to develop and apply different approaches for cancer therapy. Unfortunately, most of the applied methods for cancer therapy not only have adverse side effects like toxicity and damage of healthy cells but also have a short lifetime. To this end, introducing innovative and effective methods for cancer therapy is vital and necessary. Among different potential materials, carbon nanomaterials can cope with the rising threats of cancer. Due to unique physicochemical properties of different carbon nanomaterials including carbon, fullerene, carbon dots, graphite, single-walled carbon nanotube and multi-walled carbon nanotubes, they exhibit possibilities to address the drawbacks for cancer therapy. Carbon nanomaterials are prodigious materials due to their ability in drug delivery or remedial of small molecules. Functionalization of carbon nanomaterials can improve the cancer therapy process and decrement the side effects. These exceptional traits make carbon nanomaterials as versatile and prevalent materials for application in cancer therapy. This article spotlights the recent findings in cancer therapy using carbon nanomaterials (2015-till now). Different types of carbon nanomaterials and their utilization in cancer therapy were highlighted. The plausible mechanisms for the action of carbon nanomaterials in cancer therapy were elucidated and the advantages and disadvantages of each material were also illustrated. Finally, the current problems and future challenges for cancer therapy based on carbon nanomaterials were discussed.
    Keywords:  Carbon nanomaterials; Nanomedicine; Nontoxicity; Permeability; Retention effects
    DOI:  https://doi.org/10.1016/j.bmc.2021.116493
  53. Chem Biol Drug Des. 2021 Nov 18.
    Anticancer Properties and Pharmaceutical Applications of Ginsenoside Compound K: A Review.
    Li Zhou, Zhong-Kun Li, Cong-Yuan Li, Yue-Qin Liang, Fan Yang.
      Ginsenoside compound K (CK) is the major intestinal bacterial metabolite of ginsenosides that exhibits anticancer potential in various cancer cells both in vitro and in vivo. The anticancer types, mechanisms, and effects of CK in the past decade have been summarized in this review. Briefly, CK exerts anticancer effects via multiple molecular mechanisms, including the inhibition of proliferation, invasion, and migration, the induction of apoptosis and autophagy, and anti-angiogenesis. Some signaling pathways play a significant role in related processes, such as PI3K/Akt/mTOR, JNK/MAPK pathway, and reactive oxygen species (ROS). Moreover, the effects of CK combined with nanocarriers for anticancer efficiency are discussed in this review. Furthermore, we aimed to review the research progress of CK against cancer in the past decade, which might provide theoretical support and effective reference for further research on the medicinal value of small molecules, such as CK.
    Keywords:  Anticancer Effects; Compound K; Ginsenoside; Molecular Mechanisms; Review
    DOI:  https://doi.org/10.1111/cbdd.13983
  54. Mater Today Bio. 2021 Sep;12 100154
    Localized disruption of redox homeostasis boosting ferroptosis of tumor by hydrogel delivery system.
    Xiaomin Su, Yongbin Cao, Yao Liu, Boshu Ouyang, Bo Ning, Yang Wang, Huishu Guo, Zhiqing Pang, Shun Shen.
      Ferroptosis has received ever-increasing attention due to its unparalleled mechanism in eliminating resistant tumor cells. Nevertheless, the accumulation of toxic lipid peroxides (LPOs) at the tumor site is limited by the level of lipid oxidation. Herein, by leveraging versatile sodium alginate (ALG) hydrogel, a localized ferroptosis trigger consisting of gambogic acid (GA), 2,2'-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH), and Ink (a photothermal agent), was constructed via simple intratumor injection. Upon 1064 ​nm laser irradiation, the stored AIPH rapidly decomposed into alkyl radicals (R•), which aggravated LPOs in tumor cells. Meanwhile, GA could inhibit heat shock protein 90 (HSP90) to reduce the heat resistance of tumor cells, and forcefully consume glutathione (GSH) to weaken the antioxidant capacity of cells. Systematic in vitro and in vivo experiments have demonstrated that synchronous consumption of GSH and increased reactive oxygen species (ROS) facilitated reduced expression of glutathione peroxidase 4 (GPX4), which further contributed to disruption of intracellular redox homeostasis and ultimately boosted ferroptosis. This all-in-one strategy has a highly effective tumor suppression effect by depleting and generating fatal active compounds at tumor sites, which would pave a new route for the controllable, accurate, and coordinated tumor treatments.
    Keywords:  ABTS, 2,2-Azobis (3-ethylbenzothiazoline-6-sulfonic acid); AIPH, 2,2′-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride; ALG, sodium alginate; Alkyl radicals; CCK–8, Cell counting kit-8; CLSM, confocal laser scanning microscope; DAPI, 4′,6-diamidino-2-phenylindole; DCFH-DA, 2,7-dichlorofluorescin diacetate; DFO, deferoxamine mesylate; DLS, dynamic light scattering; DMEM, Dulbecco's Modified Eagle's Medium; DTNB, 5,5′-Dithiobis-(2-nitrobenzoic acid); FBS, fetal bovine serum; Fer-1, Ferrostatin -1; Ferroptosis; GA, gambogic acid; GPX4, glutathione peroxidase 4; GSH, glutathione; Glutathione peroxidase; HE, hematoxylin eosin; HSP90, heat shock protein 90; Hydrogel; IR, inhibitory rate; LPO, lipid peroxides; NPs, nanodrugs; PTT, photothermal therapy; ROS, reactive oxygen species; Redox homeostasis; R•, alkyl radicals
    DOI:  https://doi.org/10.1016/j.mtbio.2021.100154
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