bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–10–10
63 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. p53 regulates lipid metabolism in cancer.
  2. Lactate shuttle: from substance exchange to regulatory mechanism.
  3. Cholesterol-Lowering Drugs on Akt Signaling for Prevention of Tumorigenesis.
  4. Characterization of metabolic landscape in hepatocellular carcinoma.
  5. Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression.
  6. HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells.
  7. Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy.
  8. Cancer therapeutic strategies based on metal ions.
  9. Mitochondrial-targeting nanoprodrugs to mutually reinforce metabolic inhibition and autophagy for combating resistant cancer.
  10. Molecular aspects of fructose metabolism and metabolic disease.
  11. Small-Molecule Inhibitors Overcome Epigenetic Reprogramming for Cancer Therapy.
  12. Molecular docking and simulation studies of phytocompounds derived from Centella asiatica and Andrographis paniculata against hexokinase II as mitocan agents.
  13. Criteria to make animal studies more relevant to treating human cancer.
  14. Reactive oxygen species as a double-edged sword: The role of oxidative enzymes in antitumor therapy.
  15. Mapping of mTOR drug targets: Featured platforms for anti-cancer drug discovery.
  16. BAPST. A Combo of Common use drugs as metabolic therapy of cancer-a theoretical proposal.
  17. Bio-vehicles of cytotoxic drugs for delivery to tumor specific targets for cancer precision therapy.
  18. Ginsenoside Rh2 Inhibits Glycolysis through the STAT3/c-MYC Axis in Non-Small-Cell Lung Cancer.
  19. Bacterial protein acetylation and its role in cellular physiology and metabolic regulation.
  20. Metabolic and epigenetic regulation of endoderm differentiation.
  21. The biological and pharmacological connections between diabetes and various types of cancer.
  22. Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges.
  23. Extracellular Vesicles in Bone Tumors: How to Seed in the Surroundings Molecular Information for Malignant Transformation and Progression.
  24. THE PRESENT AND FUTURE OF PERSONALIZED NUTRITION.
  25. miR-141-3p promotes the cisplatin sensitivity of osteosarcoma cell through targeting the Glutaminase (GLS)-mediated glutamine metabolism.
  26. Current theranostic approaches for metastatic cancers through hypoxia-induced exosomal packaged cargo.
  27. The strengths and limits of cannabinoids and their receptors in cancer: Insights into the role of tumorigenesis-underlying mechanisms and therapeutic aspects.
  28. Ferroptosis: A New Promising Target for Lung Cancer Therapy.
  29. Cascade Release Nanocarriers for the Triple-Negative Breast Cancer Near-Infrared Imaging and Photothermal-Chemo Synergistic Therapy.
  30. Coupling of GABA Metabolism to Mitochondrial Glucose Phosphorylation.
  31. Recent insights on tea metabolites, their biosynthesis and chemo-preventing effects: A review.
  32. Obesity, metabolic syndrome, and cancer: pathophysiological and therapeutic associations.
  33. Pharmacological inhibition of serine synthesis enhances temozolomide efficacy by decreasing O6-methylguanine DNA methyltransferase (MGMT) expression and reactive oxygen species (ROS)-mediated DNA damage in glioblastoma.
  34. Therapeutic Effects of Polyphenols on the Treatment of Colorectal Cancer by Regulating Wnt β-Catenin Signaling Pathway.
  35. The Effects of Diet and Exercise on Endogenous Estrogens and Subsequent Breast Cancer Risk in Postmenopausal Women.
  36. Respiratory Complex I dysfunction in cancer: from a maze of cellular adaptive responses to potential therapeutic strategies.
  37. Precise Subcellular Organelle Targeting for Boosting Endogenous-Stimuli-Mediated Tumor Therapy.
  38. [Molecular classification of pancreatic cancer].
  39. Regulation of glycolysis and cancer cell proliferation by PKM2 citrullination.
  40. Dualistic role of autophagy in cancer progression.
  41. Synthesis and Photothermal Effects of Intracellular Aggregating Nanodrugs Targeting Nasopharyngeal Carcinoma.
  42. Metabolic fasting stress is ameliorated in Kinin B1 receptor-deficient mice.
  43. "Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis.
  44. Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers.
  45. Co-delivery of sorafenib and crizotinib encapsulated with polymeric nanoparticles for the treatment of in vivo lung cancer animal model.
  46. Expanding the bio-catalysis scope and applied perspectives of nanocarrier immobilized asparaginases.
  47. Evolving cancer-niche interactions and therapeutic targets during bone metastasis.
  48. Proton export alkalinizes intracellular pH and reprograms carbon metabolism to drive hematopoietic progenitor growth.
  49. Ultrasound augments on-demand breast tumor radiosensitization and apoptosis through a tri-responsive combinatorial delivery theranostic platform.
  50. Multistability maintains redox homeostasis in human cells.
  51. Acylated anthocyanins: A review on their bioavailability and effects on postprandial carbohydrate metabolism and inflammation.
  52. Metal-Polyphenol-Network Coated Prussian Blue Nanoparticles for Synergistic Ferroptosis and Apoptosis via Triggered GPX4 Inhibition and Concurrent In Situ Bleomycin Toxification.
  53. Mechanisms of induction of tumors by cholesterol and potential therapeutic prospects.
  54. Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer.
  55. Multifunctional nanoreactors-integrated microneedles for cascade reaction-enhanced cancer therapy.
  56. Innate tumor-targeted nanozyme overcoming tumor hypoxia for cancer theranostic use.
  57. Polyphenols and neuroprotection: Therapeutic implications for cognitive decline.
  58. Inhibitory effect of polyphenols (phenolic acids, lignans, and stilbenes) on cancer by regulating signal transduction pathways: a review.
  59. Sophoridine: A review of its pharmacology, pharmacokinetics and toxicity.
  60. Multifaceted actions of melanin-concentrating hormone on mammalian energy homeostasis.
  61. Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents.
  62. Gas and gas-generating nanoplatforms in cancer therapy.
  63. Autophagy provides a conceptual therapeutic framework for bone metastasis from prostate cancer.
  1. Int J Biol Macromol. 2021 Oct 05. pii: S0141-8130(21)02116-4. [Epub ahead of print]192 45-54
    p53 regulates lipid metabolism in cancer.
    Ling-Li Chen, Wen-Jun Wang.
      Reprogrammed cell metabolism is a well-accepted hallmark of cancer. Metabolism changes provide energy and precursors for macromolecule biosynthesis to satisfy the survival needs of cancer cells. The specific changes in different aspects of lipid metabolism in cancer cells have been focused in recent years. These changes can affect cell growth, proliferation, differentiation and motility through affecting membranes synthesis, energy homeostasis and cell signaling. The tumor suppressor p53 plays vital roles in the control of cell proliferation, senescence, DNA repair, and cell death in cancer through various transcriptional and non-transcriptional activities. Accumulating evidences indicate that p53 also regulates cellular metabolism, which appears to contribute to its tumor suppressive functions. Particularly the role of p53 in regulating lipid metabolism has gained more and more attention in recent decades. In this review, we summarize recent advances in the function of p53 on lipid metabolism in cancer. Further understanding and research on the role of p53 in lipid metabolism regulation will provide a potential therapeutic window for cancer treatment.
    Keywords:  Cancer; Fatty acid oxidation; Ferroptosis; Lipid metabolism; p53
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.09.188
  2. Hum Cell. 2021 Oct 04.
    Lactate shuttle: from substance exchange to regulatory mechanism.
    Xingchen Wang, He Liu, Yingqian Ni, Peibo Shen, Xiuzhen Han.
      Lactate, as the product of glycolytic metabolism and the substrate of energy metabolism, is an intermediate link between cancer cell and tumor microenvironment metabolism. The exchange of lactate between the two cells via mono-carboxylate transporters (MCTs) is known as the lactate shuttle in cancer. Lactate shuttle is the core of cancer cell metabolic reprogramming between two cells such as aerobic cancer cells and hypoxic cancer cells, tumor cells and stromal cells, cancer cells and vascular endothelial cells. Cancer cells absorb lactate by mono-carboxylate transporter 1 (MCT1) and convert lactate to pyruvate via intracellular lactate dehydrogenase B (LDH-B) to maintain their growth and metabolism. Since lactate shuttle may play a critical role in energy metabolism of cancer cells, components related to lactate shuttle may be a crucial target for tumor antimetabolic therapy. In this review, we describe the lactate shuttle in terms of both substance exchange and regulatory mechanisms in cancer. Meanwhile, we summarize the difference of key proteins of lactate shuttle in common types of cancer.
    Keywords:  Glycolysis; LDH; Lactate shuttle; MCT; Metabolic reprogramming
    DOI:  https://doi.org/10.1007/s13577-021-00622-z
  3. Front Genet. 2021 ;12 724149
    Cholesterol-Lowering Drugs on Akt Signaling for Prevention of Tumorigenesis.
    Navneet Kumar, Chandi C Mandal.
      Cholesterol has been reported to be accumulated in cancer cells. The metabolic dysregulation of the cholesterol is associated with tumor development and progression. The cholesterol-lowering drugs have been found to be involved in the prevention and treatment of various cancers. Akt, a serine/threonine kinase, can modulate the role of several downstream proteins involved in cell proliferation, migration, invasion, metabolism, and apoptosis. Since its involvement in several signaling pathways, its dysregulation is commonly reported in several cancers. Thus, targeting Akt could be an effective approach for cancer prevention and therapy. Cholesterol-lowering drugs have been found to affect the expression of Akt, and its activation in the cancer cells and thus have shown anticancer activity in different type of cancers. These drugs act on various signaling pathways such as PTEN/Akt, PI3k/Akt, Akt/NF-κB, Akt/FOXO1, Akt/mTOR, etc., which will be discussed in this article. This review article will discuss the significance of cholesterol in cancer cells, cholesterol-lowering drugs, the role of Akt in cancer cells, and the effects of cholesterol-lowering drugs on Akt in the prevention of therapy resistance and metastasis.
    Keywords:  Akt signaling; cancer; cholesterol; cholesterol-lowering drugs; fenofibrate; statins
    DOI:  https://doi.org/10.3389/fgene.2021.724149
  4. World J Gastrointest Oncol. 2021 Sep 15. 13(9): 1144-1156
    Characterization of metabolic landscape in hepatocellular carcinoma.
    Jing Wu, Ran Xue, Rong-Tao Jiang, Qing-Hua Meng.
      Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, accounting for approximately 75%-85% of primary liver cancers. Metabolic alterations have been labeled as an emerging hallmark of tumors. Specially, the last decades have registered a significant improvement in our understanding of the role of metabolism in driving the carcinogenesis and progression of HCC. In this paper, we provide a review of recent studies that investigated the metabolic traits of HCC with a specific focus on three common metabolic alterations involving glycolysis, lipid metabolism, and glutamine addiction which have been gaining much attention in the field of HCC. Next, we describe some representative diagnostic markers or tools, and promising treatment agents that are proposed on the basis of the aforementioned metabolic alterations for HCC. Finally, we present some challenges and directions that may promisingly speed up the process of developing objective diagnostic markers and therapeutic options underlying HCC. Specifically, we recommend future investigations to carefully take into account the influence of heterogeneity, control for study-specific confounds, and invite the validation of existing biomarkers.
    Keywords:  Diagnosis and treatment; Glutamine addiction; Glycolysis; Hepatocellular carcinoma; Lipid metabolism; Metabolic reprogramming
    DOI:  https://doi.org/10.4251/wjgo.v13.i9.1144
  5. Pharmacol Ther. 2021 Oct 01. pii: S0163-7258(21)00194-7. [Epub ahead of print] 107992
    Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression.
    Shiyao Sui, Shouping Xu, Da Pang.
      Breast cancer has become a serious threat to women's health. Cancer progression is mainly derived from resistance to apoptosis induced by procedures or therapies. Therefore, new drugs or models that can overcome apoptosis resistance should be identified. Ferroptosis is a recently identified mode of cell death characterized by excess reactive oxygen species-induced lipid peroxidation. Since ferroptosis is distinct from apoptosis, necrosis and autophagy, its induction successfully eliminates cancer cells that are resistant to other modes of cell death. Therefore, ferroptosis may become a new direction around which to design breast cancer treatment. Unfortunately, the complete appearance of ferroptosis in breast cancer has not yet been fully elucidated. Furthermore, whether ferroptosis inducers can be used in combination with traditional anti- breast cancer drugs is still unknown. Moreover, a summary of ferroptosis in breast cancer progression and therapy is currently not available. In this review, we discuss the roles of ferroptosis-associated modulators glutathione, glutathione peroxidase 4, iron, nuclear factor erythroid-2 related factor-2, superoxide dismutases, lipoxygenase and coenzyme Q in breast cancer. Furthermore, we provide evidence that traditional drugs against breast cancer induce ferroptosis, and that ferroptosis inducers eliminate breast cancer cells. Finally, we put forward prospect of using ferroptosis inducers in breast cancer therapy, and predict possible obstacles and corresponding solutions. This review will deepen our understanding of the relationship between ferroptosis and breast cancer, and provide new insights into breast cancer-related therapeutic strategies.
    Keywords:  Breast cancer; Coenzyme Q; Ferroptosis; Glutathione; Glutathione peroxidase 4; Iron; Lipoxygenase; Nuclear factor erythroid-2 related factor-2; Superoxide dismutases
    DOI:  https://doi.org/10.1016/j.pharmthera.2021.107992
  6. Redox Biol. 2021 Sep 25. pii: S2213-2317(21)00309-8. [Epub ahead of print]47 102149
    HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells.
    Thais Oliveira, Evan Hermann, Daniel Lin, Winyoo Chowanadisai, Elizabeth Hull, McKale Montgomery.
      Epithelial-to-mesenchymal transition (EMT) is an essential mechanism for development and wound healing, but in cancer it also mediates the progression and spread of aggressive tumors while increasing therapeutic resistance. Adoption of a mesenchymal state is also associated with increased iron uptake, but the relationship between EMT and the key regulators of cellular iron metabolism remains undefined. In this regard, the human adrenal cortical carcinoma SW13 cell line represents an invaluable research model as HDAC inhibitor treatment can convert them from an epithelial-like (SW13-) cell type to a mesenchymal-like (SW13+) subtype. In this study we establish SW13 cells as a model for exploring the link between iron and EMT. Increased iron accumulation following HDAC inhibitor mediated EMT is associated with decreased expression of the iron export protein ferroportin, enhanced ROS production, and reduced expression of antioxidant response genes. As availability of redox active iron and loss of lipid peroxide repair capacity are hallmarks of ferroptosis, a form of iron-mediated cell death, we next examined whether HDAC inhibitor treatment could augment ferroptosis sensitivity. Indeed, HDAC inhibitor treatment synergistically increased cell death following induction of ferroptosis. The exact mechanisms by which HDAC inhibition facilitates cell death following ferroptosis induction requires further study. As several HDAC inhibitors are already in use clinically for the treatment of certain cancer types, the findings from these studies have immediate implications for improving iron-targeted chemotherapeutic strategies.
    Keywords:  Epithelial-to-mesenchymal transition (EMT); Ferroptosis; Histone deacetylase (HDAC) inhibitors; Iron
    DOI:  https://doi.org/10.1016/j.redox.2021.102149
  7. Front Pharmacol. 2021 ;12 730751
    Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy.
    Jianming Hu, Leyi Zhang, Wuzhen Chen, Lesang Shen, Jingxin Jiang, Shanshan Sun, Zhigang Chen.
      Accumulating evidence showed that cancer stem cells (CSCs) play significant roles in cancer initiation, resistance to therapy, recurrence and metastasis. Cancer stem cells possess the ability of self-renewal and can initiate tumor growth and avoid lethal factors through flexible metabolic reprogramming. Abnormal lipid metabolism has been reported to be involved in the cancer stemness and promote the development of cancer. Lipid metabolism includes lipid uptake, lipolysis, fatty acid oxidation, de novo lipogenesis, and lipid desaturation. Abnormal lipid metabolism leads to ferroptosis of CSCs. In this review, we comprehensively summarized the role of intra- and extracellular lipid signals in cancer stemness, and explored the feasibility of using lipid metabolism-related treatment strategies for future cancer.
    Keywords:  cancer stem cell; ferroptosis; lipid metabolism; therapeutic target; tumor environment
    DOI:  https://doi.org/10.3389/fphar.2021.730751
  8. Chem Sci. 2021 Sep 29. 12(37): 12234-12247
    Cancer therapeutic strategies based on metal ions.
    Yang Liu, Yinghui Wang, Shuyan Song, Hongjie Zhang.
      As a necessary substance to maintain the body's normal life activities, metal ions are ubiquitous in organisms and play a major role in various complex physiological and biochemical processes, such as material transportation, energy conversion, information transmission, metabolic regulation, etc. Their abnormal distribution/accumulation in cells can interfere with these processes, causing irreversible physical damage to cells or activating biochemical reactions to induce cell death. Therefore, metal ions can be exploited against a wide spectrum of cancers with high efficiency and without drug resistance, which can effectively inhibit the growth of cancer cells by triggering biocatalysis, breaking the osmotic balance, affecting metabolism, interfering with signal transduction, damaging DNA, etc. This perspective systematically summarizes the latest research progress of metal ion-based anti-tumor therapy, and emphasizes the challenges and development directions of this type of therapeutic strategy, hoping to provide a general implication for future research.
    DOI:  https://doi.org/10.1039/d1sc03516a
  9. Biomaterials. 2021 Sep 28. pii: S0142-9612(21)00525-1. [Epub ahead of print]278 121168
    Mitochondrial-targeting nanoprodrugs to mutually reinforce metabolic inhibition and autophagy for combating resistant cancer.
    Min Sun, Congyu Wang, Mingchen Lv, Zhen Fan, Jianzhong Du.
      Abnormal energy metabolism is one of the hallmarks of cancer and closely linked to therapy resistance. However, existing metabolic inhibitors suffer from inefficient cell enrichment and therapeutic effects. In this work, we developed an effective strategy to mutually reinforce the metabolic inhibition and autophagy for enhanced tumor killing efficacy and combating resistant cancer. First, mitochondrial homing moiety triphenylphosphonium and metabolic inhibitor lonidamine were grafted onto polylysine. After self-assembly of this functionalized polylysine, ferrocene and glucose oxidase were immobilized to afford additional chemotherapy functions, and the final product was named as FG/T-Nanoprodrug. Effective mitochondrial targeting and metabolic inhibition were observed in resistant cancer cells. In addition, owing to the inhibited metabolism, less glucose is consumed to allow FG/T-Nanoprodrug to produce excess reactive oxygen species (ROS) by glucose oxidase and ferrocene. The enhanced chemodynamic therapy increases the mitochondrial permeability to promote the release of cytochrome c from mitochondria, ultimately induces high levels of autophagy. The FG/T-Nanoprodrug demonstrated superior mutually reinforcing of metabolic inhibition (up to 3.7-fold compared to free lonidamine) and autophagy (up to 125.3-fold compared to free lonidamine) to effectively kill resistant cancer cell both in vitro and in vivo. Overall, this strategy could pave a new way to efficient treatment of resistant cancer and other metabolically abnormal diseases.
    Keywords:  Autophagy; Chemodynamic therapy; Lonidamine; Nanoprodrug; Polylysine
    DOI:  https://doi.org/10.1016/j.biomaterials.2021.121168
  10. Cell Metab. 2021 Sep 28. pii: S1550-4131(21)00429-0. [Epub ahead of print]
    Molecular aspects of fructose metabolism and metabolic disease.
    Mark A Herman, Morris J Birnbaum.
      Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of obesity and the associated cardiometabolic disease. Sugar is added to the diet in the form of sucrose or high-fructose corn syrup, both of which comprise nearly equal amounts of glucose and fructose. The unique aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as a physiological signal of normal dietary sugar consumption. However, when fructose is consumed in excess, these unique properties may contribute to the pathogenesis of cardiometabolic disease. Here, we review the biochemistry, genetics, and physiology of fructose metabolism and consider mechanisms by which excessive fructose consumption may contribute to metabolic disease. Lastly, we consider new therapeutic options for the treatment of metabolic disease based upon this knowledge.
    Keywords:  ALDOB; ChREBP; GLUT5; KHK; NAFLD; TKFC; cardiometabolic disease; fructose; insulin resistance; lipogenesis; steatosis; uric acid
    DOI:  https://doi.org/10.1016/j.cmet.2021.09.010
  11. Front Pharmacol. 2021 ;12 702360
    Small-Molecule Inhibitors Overcome Epigenetic Reprogramming for Cancer Therapy.
    Wenjing Xiao, Qiaodan Zhou, Xudong Wen, Rui Wang, Ruijie Liu, Tingting Wang, Jianyou Shi, Yonghe Hu, Jun Hou.
      Cancer treatment is a significant challenge for the global health system, although various pharmacological and therapeutic discoveries have been made. It has been widely established that cancer is associated with epigenetic modification, which is reversible and becomes an attractive target for drug development. Adding chemical groups to the DNA backbone and modifying histone proteins impart distinct characteristics on chromatin architecture. This process is mediated by various enzymes modifying chromatin structures to achieve the diversity of epigenetic space and the intricacy in gene expression files. After decades of effort, epigenetic modification has represented the hallmarks of different cancer types, and the enzymes involved in this process have provided novel targets for antitumor therapy development. Epigenetic drugs show significant effects on both preclinical and clinical studies in which the target development and research offer a promising direction for cancer therapy. Here, we summarize the different types of epigenetic enzymes which target corresponding protein domains, emphasize DNA methylation, histone modifications, and microRNA-mediated cooperation with epigenetic modification, and highlight recent achievements in developing targets for epigenetic inhibitor therapy. This article reviews current anticancer small-molecule inhibitors targeting epigenetic modified enzymes and displays their performances in different stages of clinical trials. Future studies are further needed to address their off-target effects and cytotoxicity to improve their clinical translation.
    Keywords:  cancer biomarker; epigenetic drugs; epigenetic reprogramming; histone modification; microRNA; small-molecule inhibitors
    DOI:  https://doi.org/10.3389/fphar.2021.702360
  12. Mitochondrion. 2021 Oct 01. pii: S1567-7249(21)00139-2. [Epub ahead of print]
    Molecular docking and simulation studies of phytocompounds derived from Centella asiatica and Andrographis paniculata against hexokinase II as mitocan agents.
    Geeta Swargiary, Shalini Mani.
      Hexokinase II (HK2), a glycolytic enzyme is commonly overexpressed in most cancer types. The overexpression of HK2 is reported to promote the survival of cancer cells by facilitating the constant ATP generation and protecting the cancer cell against apoptotic cell death. Hence, HK2 is considered as potential target of many mitochondria targeting anticancerous agents (referred to as mitocans). Most of the existing mitocans are synthetic and hence such compounds are observed to exhibit adverse effects, witnessed through many experimental outcomes. These limitations necessitates hunting for an alternative source of mitocans with minimum/no side effects. The need for an alternative therapy points towards the ethnomedicinal herbs, known for their minimal side effects and effectiveness. Henceforth recent studies have put forth the effort to utilize anticancer herbs in formulating naturally derived mitocans as an add-on to improve cancer therapeutics. So, our study aims to explore the HK2 targeting potential of phytocompounds from the selected anticancerous herbs Andrographis paniculata (AP) and Centella asiatica (CA). 60 phytocompounds collectively from CA and AP were docked against HK2 and drug-likeness prediction of the selected phytocompounds was performed to screen the best possible ligand for HK2. Furthermore, the docked complexes were subjected to molecular dynamics simulations (MDS) to analyse the molecular mechanism of protein-ligand interactions. The results of the study suggest that the natural compounds asiatic acid and bayogenin (from CA) and andrographolide (from AP) can bepotential natural mitocans by targeting HK2. Further experimental studies (in-vitro and in-vivo) are required to validate the results.
    Keywords:  Andrographis paniculata; Andrographolide; Asiatic acid; Bayogenin; Centella asiatica; Hexokinase II; Molecular docking; Molecular dynamics simulation
    DOI:  https://doi.org/10.1016/j.mito.2021.09.013
  13. Curr Opin Immunol. 2021 Oct 04. pii: S0952-7915(21)00120-5. [Epub ahead of print]74 25-31
    Criteria to make animal studies more relevant to treating human cancer.
    Steven P Wolf, Frank T Wen, Hans Schreiber.
      Certain aspects of experimental tumor models in mice most accurately reflect the biology and immunology of cancer in patients. A survey of experimental cancer immunotherapy papers published in 2020 shows most do not achieve cancer shrinkage although treatment is initiated at an early time point after cancer cell injection, which does not reflect cancer immunotherapy in patients. Even then, few current experimental approaches eradicate the injected malignant cells, most only delay outgrowth. The value of targeting mutation-encoded tumor-specific antigens becomes increasingly evident while problems of finding normal gene-encoded tumor-associated antigens as safe, effective targets persist. It might be time to refocus on realistic experimental settings and truly cancer-specific targets. These antigens are associated with the least risk of side effects.
    DOI:  https://doi.org/10.1016/j.coi.2021.09.002
  14. Biofactors. 2021 Oct 04.
    Reactive oxygen species as a double-edged sword: The role of oxidative enzymes in antitumor therapy.
    Elena Rosini, Loredano Pollegioni.
      A number of approaches have been developed over the years to manage cancer, such as chemotherapy using low-molecular-mass molecules and radiotherapy. Here, enzymes can also find useful applications. Among them, oxidases have attracted attention because of their ability to produce reactive oxygen species (ROS, especially hydrogen peroxide) in tumors and potentially modulate the production of this cytotoxic compound when enzymes active on substrates present in low amounts are used, such as the d-amino acid oxidase and d-amino acid couple system. These treatments have been also developed for additional cancer treatment approaches, such as phototherapy, nutrient starvation, and metal-induced hydroxyl radical production. In addition, to improve tumor specificity and decrease undesired side effects, oxidases have been targeted by means of nanotechnologies and protein engineering (i.e., by designing chimeric proteins able to accumulate in the tumor). The most recent advances obtained by using six different oxidases (i.e., the FAD-containing enzymes glucose oxidase, d- and l-amino acid oxidases, cholesterol oxidase and xanthine oxidase, and the copper-containing amine oxidase) have been reported. Anticancer therapy based on oxidase-based ROS production has now reached maturity and can be applied in the clinic.
    Keywords:  cancer therapy; cytotoxicity; drug delivery; enzyme prodrug therapy; flavoprotein oxidases; nanoparticles; nanoreactors; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1002/biof.1789
  15. Pharmacol Ther. 2021 Oct 05. pii: S0163-7258(21)00214-X. [Epub ahead of print] 108012
    Mapping of mTOR drug targets: Featured platforms for anti-cancer drug discovery.
    Raef Shams, Yoshihiro Ito, Hideyuki Miyatake.
      The mammalian/mechanistic target of rapamycin (mTOR) is a regulatory protein kinase involved in cell growth and proliferation. mTOR is usually assembled in two different complexes with different regulatory mechanisms, mTOR complex 1 (mTORC1) and mTORC2, which are involved in different functions such as cell proliferation and cytoskeleton assembly, respectively. In cancer cells, mTOR is hyperactivated in response to metabolic alterations and/or oncogenic signals to overcome the stressful microenvironments. Therefore, recent research progress for mTOR inhibition involves a variety of compounds that have been developed to disturb the metabolic processes of cancer cells through mTOR inhibition. In addition to competitive or allosteric inhibition, a new inhibition strategy that emerged mTOR complexes destabilization has recently been a concern. Here, we review the history of mTOR and its inhibition, along with the timeline of the mTOR inhibitors. We also introduce prospective drug targets to inhibit mTOR by disrupting the complexation of the components with peptides and small molecules.
    Keywords:  Cancer therapy; Drug target; mTOR; mTOR inhibitors generations; mTORC1/2 destabilizers
    DOI:  https://doi.org/10.1016/j.pharmthera.2021.108012
  16. Curr Mol Pharmacol. 2021 Oct 06.
    BAPST. A Combo of Common use drugs as metabolic therapy of cancer-a theoretical proposal.
    Adriana Romo-Perez, Guadalupe Dominguez-Gomez, Alma Chavez-Blanco, Lucia Taja-Chayeb, Aurora Gonzalez-Fierro, Elisa Garcia Martinez, Jose Correa-Basurto, Alfonso Duenas-Gonzalez.
      Advances in cancer therapy have yet to impact worldwide cancer mortality. Poor cancer drug affordability is one of the factors limiting mortality burden strikes. Up to now, cancer drug repurposing had no meet expectations concerning drug affordability. The three FDA-approved cancer drugs developed under repurposing -all-trans-retinoic acid, arsenic trioxide, and thalidomide- do not differ in price from other drugs developed under the classical model. Though additional factors affect the whole process from inception to commercialization, the repurposing of widely used, commercially available, and cheap drugs may help. This work reviews the concept of the malignant metabolic phenotype and its exploitation by simultaneously blocking key metabolic processes altered in cancer. We elaborate on a combination called BAPST, which stands for the following drugs and pathways they inhibit: Benserazide (glycolysis), Apomorphine (glutaminolysis), Pantoprazole (Fatty-acid synthesis), Simvastatin (mevalonate pathway), and Trimetazidine (Fatty-acid oxidation). Their respective primary indications are: • Parkinson's disease (benserazide and apomorphine). • Peptic ulcer disease (pantoprazole). • Hypercholesterolemia (simvastatin). • Ischemic heart disease (trimetazidine). When used for their primary indication, the literature review on each of these drugs shows they have a good safety profile and lack predicted pharmacokinetic interaction among them. Most importantly, the inhibitory enzymatic concentrations required for inhibiting their cancer targets enzymes are below the plasma concentrations observed when these drugs are used for their primary indication. Based on that, we propose that the regimen BAPTS merits preclinical testing.
    Keywords:  cancer drug repurposing; de novo fatty-acid synthesis; fatty-acid oxidation; glutaminolysis; glycolysis; mevalonate pathway
    DOI:  https://doi.org/10.2174/1874467214666211006123728
  17. Biomed Pharmacother. 2021 Oct 01. pii: S0753-3322(21)01044-1. [Epub ahead of print]144 112260
    Bio-vehicles of cytotoxic drugs for delivery to tumor specific targets for cancer precision therapy.
    Layla Al-Mansoori, Philip Elsinga, Sayed K Goda.
      Abnormal structural and molecular changes in malignant tissues were thoroughly investigated and utilized to target tumor cells, hence rescuing normal healthy tissues and lowering the unwanted side effects as non-specific cytotoxicity. Various ligands for cancer cell specific markers have been uncovered and inspected for directional delivery of the anti-cancer drug to the tumor site, in addition to diagnostic applications. Over the past few decades research related to the ligand targeted therapy (LTT) increased tremendously aiming to treat various pathologies, mainly cancers with well exclusive markers. Malignant tumors are known to induce elevated levels of a variety of proteins and peptides known as cancer "markers" as certain antigens (e.g., Prostate specific membrane antigen "PSMA", carcinoembryonic antigen "CEA"), receptors (folate receptor, somatostatin receptor), integrins (Integrin αvβ3) and cluster of differentiation molecules (CD13). The choice of an appropriate marker to be targeted and the design of effective ligand-drug conjugate all has to be carefully selected to generate the required therapeutic effect. Moreover, since some tumors express aberrantly high levels of more than one marker, some approaches investigated targeting cancer cells with more than one ligand (dual or multi targeting). We aim in this review to report an update on the cancer-specific receptors and the vehicles to deliver cytotoxic drugs, including recent advancements on nano delivery systems and their implementation in targeted cancer therapy. We will discuss the advantages and limitations facing this approach and possible solutions to mitigate these obstacles. To achieve the said aim a literature search in electronic data bases (PubMed and others) using keywords "Cancer specific receptors, cancer specific antibody, tumor specific peptide carriers, cancer overexpressed proteins, gold nanotechnology and gold nanoparticles in cancer treatment" was carried out.
    Keywords:  CRISPR for cancer therapy; Cancer overexpressed proteins; Cancer specific antibody; Cancer specific receptors; Cancer stem cells; Targeted cancer strategies; Tumor specific peptide carriers; mRNA vaccine for cancer therapy
    DOI:  https://doi.org/10.1016/j.biopha.2021.112260
  18. J Oncol. 2021 ;2021 9715154
    Ginsenoside Rh2 Inhibits Glycolysis through the STAT3/c-MYC Axis in Non-Small-Cell Lung Cancer.
    Xiaodan Sun, Peiyan Zhao, Hui Li, Yan Liu, Tianming Wang, Ying Cheng.
      Ginsenoside Rh2 (Rh2) is one of the pharmacologically active components of ginseng with an antitumor effect. However, its effect on non-small-cell lung cancer (NSCLC), especially on aerobic glycolysis, which plays a crucial role in the proliferation and progression of tumor cells, has not been characterized. Here, we demonstrated that Rh2 inhibited the proliferation and metastasis of NSCLC cells by promoting apoptosis and suppressing epithelial-mesenchymal transition, respectively. Notably, Rh2 exerted a glycolysis inhibition effect through regulating GLUT1, PKM2, and LDHA, which are key enzymes of the glycolysis process. Furthermore, the metabolic shift function of Rh2 was dependent on the STAT3/c-Myc axis in NSCLC. This novel regulatory role of Rh2 provides a new perspective for NSCLC treatment and highlights the potentiality of Rh2 to be used as a tumor energy blocker. The combination of Rh2 with an STAT3 or c-Myc inhibitor revealed a promising therapeutic approach for patients with NSCLC.
    DOI:  https://doi.org/10.1155/2021/9715154
  19. Biotechnol Adv. 2021 Oct 05. pii: S0734-9750(21)00148-8. [Epub ahead of print] 107842
    Bacterial protein acetylation and its role in cellular physiology and metabolic regulation.
    Min Liu, Likun Guo, Yingxin Fu, Meitong Huo, Qingsheng Qi, Guang Zhao.
      Protein acetylation is an evolutionarily conserved posttranslational modification. It affects enzyme activity, metabolic flux distribution, and other critical physiological and biochemical processes by altering protein size and charge. Protein acetylation may thus be a promising tool for metabolic regulation to improve target production and conversion efficiency in fermentation. Here we review the role of protein acetylation in bacterial physiology and metabolism and describe applications of protein acetylation in fermentation engineering and strategies for regulating acetylation status. Although protein acetylation has become a hot topic, the regulatory mechanisms have not been fully characterized. We propose future research directions in protein acetylation.
    Keywords:  Acetyl phosphate; Carbon catabolite repression; Cellular physiology; Metabolic regulation; Posttranslational modification; Protein acetylation
    DOI:  https://doi.org/10.1016/j.biotechadv.2021.107842
  20. Trends Cell Biol. 2021 Oct 01. pii: S0962-8924(21)00181-1. [Epub ahead of print]
    Metabolic and epigenetic regulation of endoderm differentiation.
    Yi Fang, Xiaoling Li.
      The endoderm, one of the three primary germ layers, gives rise to lung, liver, stomach, intestine, colon, pancreas, bladder, and thyroid. These endoderm-originated organs are subject to many life-threatening diseases. However, primary cells/tissues from endodermal organs are often difficult to grow in vitro. Human pluripotent stem cells (hPSCs), therefore, hold great promise for generating endodermal cells and their derivatives for the development of new therapeutics against these human diseases. Although a wealth of research has provided crucial information on the mechanisms underlying endoderm differentiation from hPSCs, increasing evidence has shown that metabolism, in connection with epigenetics, actively regulates endoderm differentiation in addition to the conventional endoderm inducing signals. Here we review recent advances in metabolic and epigenetic regulation of endoderm differentiation.
    Keywords:  endoderm differentiation; endodermal gene expression; epigenetic remodeling; histone crotonylation; metabolic switch
    DOI:  https://doi.org/10.1016/j.tcb.2021.09.002
  21. Pathol Res Pract. 2021 Sep 29. pii: S0344-0338(21)00302-2. [Epub ahead of print]227 153641
    The biological and pharmacological connections between diabetes and various types of cancer.
    Xuechang Wang, Suming Ding.
      Diabetes and cancer incidence have risen tremendously over the years. Additionally, both cancer and diabetes share numerous risks, such as overweight, inactive lifestyles, older age, and smoking. Numerous methods have been suggested to connect obesity and diabetes to cancer advancements, such as increasing insulin/ Insulin-like growth factor I (IGF-1) signaling, lipid and glucose uptake and metabolism, shifts in the cytokine, chemokine, and adipokine profile also variations in the adipose tissue immediately adjacent to cancer spots. Diabetes has been found to have a complicated cancer-causing mechanism involving excessive reactive oxygen species (ROS) production, loss of critical macromolecules, chronic inflammation, and delayed repair, all of which contribute to carcinogenesis. Diabetes-associated epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition lead to the formation of cancer-associated fibroblasts in tumors by enabling tumor cells to extravasate via the endothelium and epithelium. This study aims to describe the correlation between diabetes and cancer, as well as summarize the molecular connections and shared pathways such as sex hormones, hyperglycemia, inflammation, insulin axis, metabolic symbiosis, and endoplasmic reticulum (ER) stress that exist between them.
    Keywords:  Biologic pathway; Cancer; Diabetes; Insulin; Malignancy
    DOI:  https://doi.org/10.1016/j.prp.2021.153641
  22. Mol Cancer. 2021 Oct 04. 20(1): 128
    Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges.
    Daolin Tang, Guido Kroemer, Rui Kang.
      Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.
    Keywords:  Covalent inhibitor; Drug resistance; Gene mutation; KRAS; Targeted therapy
    DOI:  https://doi.org/10.1186/s12943-021-01422-7
  23. Front Oncol. 2021 ;11 722922
    Extracellular Vesicles in Bone Tumors: How to Seed in the Surroundings Molecular Information for Malignant Transformation and Progression.
    Alfredo Cappariello, Nadia Rucci.
      Bone is a very dynamic tissue hosting different cell types whose functions are regulated by a plethora of membrane-bound and soluble molecules. Intercellular communication was recently demonstrated to be also sustained by the exchange of extracellular vesicles (EVs). These are cell-derived nanosized structures shuttling biologically active molecules, such as nucleic acids and proteins. The bone microenvironment is a preferential site of primary and metastatic tumors, in which cancer cells find a fertile soil to "seed and blossom". Nowadays, many oncogenic processes are recognized to be sustained by EVs. For example, EVs can directly fuel the vicious cycle in the bone/bone marrow microenvironment. EVs create a favourable environment for tumor growth by affecting osteoblasts, osteoclasts, osteocytes, adipocytes, leukocytes, and endothelial cells. At the same time other crucial tumor-mediated events, such as the premetastatic niche formation, tumor cell dormancy, as well as drug resistance, have been described to be fostered by tumor-derived EVs. In this review, we will discuss the main body of literature describing how the cancer cells use the EVs for their growth into the bone and for educating the bone microenvironment to host metastases.
    Keywords:  bone tumor; dormancy; drug resistance; extracellular vesicles; premetastatic niche; vicious cycle
    DOI:  https://doi.org/10.3389/fonc.2021.722922
  24. Rev Invest Clin. 2021 ;73(5): 321-325
    THE PRESENT AND FUTURE OF PERSONALIZED NUTRITION.
    Nimbe Torres, Armando R Tovar.
      In recent decades, there has been an increase in the presence of metabolic disorders associated with obesity. Central in the treatment of these conditions, including abnormalities in glucose and lipid metabolism, dietary strategies play an important role. However, dietary recommendations are based on the generalization of nutrient or food intake response for all individuals, which not necessarily impacts the health of all individuals. The concept of personalized nutrition or precision nutrition has been recently developed, which states that diet is not the only factor accountable for metabolic responses such as postprandial glucose peaks, but that other factors are also involved, one of the most important of which is the gut microbiota. Therefore, the future of nutritional interventions is to generate algorithms based on the type of food consumed, biochemical parameters, physical activity, genetic variability, and especially the gut microbiota to predict the type of diet a person requires according to his or her metabolic alterations.
    Keywords:  Microbiota and nutrition; Nutrigenomics; Personalized nutrition; Precision nutrition
    DOI:  https://doi.org/10.24875/RIC.21000346
  25. Curr Mol Med. 2021 Oct 04.
    miR-141-3p promotes the cisplatin sensitivity of osteosarcoma cell through targeting the Glutaminase (GLS)-mediated glutamine metabolism.
    Xueli Zhou, Panpan Wei, Xinju Wang, Jianguo Zhang, Yulin Shi.
       AIMS: This study aimed to evaluate the roles and molecular targets of miRNA-141-3p in the cisplatin sensitivity of osteosarcoma.
    BACKGROUND: Osteosarcoma is one of the most common-type bone tumors, occurring mainly in children and adolescent. Cancer cells display dysregulated cellular metabolism, such as the abnormally elevated glutamine metabolism.
    OBJECTIVE: Non-coding RNA miRNA-141-3p has been reported to act as a tumor suppressor in osteosarcoma. Currently, the precise molecular mechanisms for the miR-141-3p-mediated chemosensitivity through regulating glutamine metabolism remain unclear.
    METHODS: We collected thirty-paired OS tumors and their adjacent normal tissues. The osteosarcoma cell lines [Saos-2] and normal osteoblast cells, hFOB1.19 were used for in vitro experiments. RT-qPCR and Western blot were applied for gene expression detections. Targets of miR-141-3p was predicted from starBase. The MTT and flow cytometric assays were performed to determine cell growth and apoptosis rates. The cellular glutamine metabolism was monitored by glutamine uptake assay and the glutaminase [GLS] activity assay.
    RESULTS: We report miR-141-3p were significantly downregulated in osteosarcoma tissues and cells. Overexpression of miR-141-3p suppressed OS cell growth and sensitized OS cells to cisplatin. In addition, glutamine metabolism was significantly increased in osteosarcoma. We characterized that GLS played oncogenic roles in osteosarcoma and validated GLS was a direct target of miR-141-3p in OS cells. Specifically, rescue experiments consistently demonstrated the miR-141-3p-promoted cisplatin sensitivity was through direct targeting GLS.
    CONCLUSION: Overall, our findings revealed new molecular mechanisms of the miR-141-3p-modulated cisplatin sensitization through targeting the GLS-glutamine metabolism pathway. This study will contribute to developing new therapeutic approaches for the treatments of chemoresistant osteosarcoma.
    Keywords:  Cisplatin resistance; Glutaminase; Osteosarcoma; glutamine; metabolism; miR-141-3p
    DOI:  https://doi.org/10.2174/1566524021666211004112055
  26. Life Sci. 2021 Oct 04. pii: S0024-3205(21)01004-3. [Epub ahead of print] 120017
    Current theranostic approaches for metastatic cancers through hypoxia-induced exosomal packaged cargo.
    Manisha Singh, Shriya Agarwal, Vinayak Agarwal, Shweta Mall, Pranav Pancham, Shalini Mani.
      Tumour cells exhibit numerous defence mechanisms against various therapeutic strategies and help in developing drug resistance. These defence strategies help cancer cells prevent their elimination from an organism and prosper at a specific location. In recent times it's been observed that there is a significant contribution of secreted extracellular vesicles (EVs) from such tumorigenic sites in the development and prognosis of cancer. Amongst the various types of EVs, exosomes behave like biological carriers, play a crucial role in transporting the content between different cells, and had such an underrated defence mode by getting induced due to the hypoxia secreted highly specialised double-membrane structures. These small structure vesicles play a critical part in regulating local microenvironment and intracellular communications, cited by many research studies. Exosomes are a potential carrier of several cargo biomolecules like proteins, lipids, miRNAs, mRNAs etc., facilitating better communication within the microenvironment of cancer cells, enhancing the metastatic rate along with cancer progression. Several studies have extensively researched elucidating exosomes mediated radiation-induced bystander effects: multidrug resistance, epithelial-mesenchymal transition, and help cancer cells escape from the immune system apart from playing a critical role in angiogenesis too. Due to its natural tendency to carry different biomolecules, it can also be used to haul chemical drugs and efficiently deliver the drug molecules to the targeted site of cancer. The current review aims to explore the vivid role of hypoxia-induced exosomes in tumour progression along with its application and challenges in cancer therapeutics.
    Keywords:  Angiogenesis; Biosynthesis; Extracellular vesicles (EVs); Hypoxia induced factors (HIF); Immunotherapy; Melanoma inhibitory activity (MIA)
    DOI:  https://doi.org/10.1016/j.lfs.2021.120017
  27. Biomed Pharmacother. 2021 Oct 05. pii: S0753-3322(21)01063-5. [Epub ahead of print]144 112279
    The strengths and limits of cannabinoids and their receptors in cancer: Insights into the role of tumorigenesis-underlying mechanisms and therapeutic aspects.
    Fatemeh Hosami, Maryam Haghparast Ghadimkhah, Vahid Salimi, Seyedeh Sara Ghorbanhosseini, Masoumeh Tavakoli-Yaraki.
      Cancer, as a mysterious and complex disease, has a multi-stage molecular process that uses the cellular molecular machine and multiple signaling pathways to its advantage. Cannabinoids, as terpenophenolic compounds and their derivatives, showed influences on immune system responses, inflammation, and cell growth that have sparked a growing interest in exploring their effects on cancer cell fate, as well. A large body of evidence in experimental models indicating the involvement of cannabinoids and their related receptors in cancer cell growth, development, and fate. In accordance, the present study provided insights regarding the strengths and limits of cannabinoids and their receptors in critical steps of tumorigenesis and its underlying molecular pathways such as; cancer cell proliferation, type of cell death pathway, angiogenesis, invasion, metastasis and, immune system response. Based on the results of the present study and due to the contribution of cannabinoids in various cancer cell growth control processes, these compounds cancer can be considered worthwhile in finding new alternatives for cancer therapy.
    Keywords:  Angiogenesis; Cancer; Cannabinoid receptor; Cannabinoids; Immune system; Proliferation
    DOI:  https://doi.org/10.1016/j.biopha.2021.112279
  28. Oxid Med Cell Longev. 2021 ;2021 8457521
    Ferroptosis: A New Promising Target for Lung Cancer Therapy.
    Rui Xiong, Ruyuan He, Bohao Liu, Wenyang Jiang, Bo Wang, Ning Li, Qing Geng.
      Ferroptosis is a new type of regulatory cell death that differs from autophagy, apoptosis, necrosis, and pyroptosis; it is caused primarily by the accumulation of iron and lipid peroxides in the cell. Studies have shown that many classical signaling pathways and biological processes are involved in the process of ferroptosis. In recent years, investigations have revealed that ferroptosis plays a crucial role in the progression of tumors, especially lung cancer. In particular, inducing ferroptosis in cells can inhibit the growth of tumor cells, thereby reversing tumorigenesis. In this review, we summarize the characteristics of ferroptosis from its underlying basis and role in lung cancer and provide possible applications for it in lung cancer therapies.
    DOI:  https://doi.org/10.1155/2021/8457521
  29. Front Oncol. 2021 ;11 747608
    Cascade Release Nanocarriers for the Triple-Negative Breast Cancer Near-Infrared Imaging and Photothermal-Chemo Synergistic Therapy.
    Ke Li, Ruyue Li, Baona Zhou, Jing Chen, Kai Lan, Wenhua Zhan, Di Chen, Tao Zhang, Xueping Li.
      Triple-negative breast cancer (TNBC) has inadequate treatment approaches and a poor prognosis. It is urgent to develop new treatment approaches for TNBC. The combination of photothermal therapy (PTT) and chemotherapy is a very effective potential therapy for TNBC. However, asynchronous accumulation, unclear efficacy, and toxic side effects hinder the further promotion of this method. Therefore, we designed and constructed a new type of nanocarriers, the cascade release near-infrared imaging (NIFI) & thermal-chemo combination nanoparticles (CNC NPs), that can release drugs through the cascade of ultrasound triggering and pH responding to achieve the synchronous tumor accumulation, monitoring and synergistic treatment of two functional molecules. The key material of CNC NPs is the polydopamine (PDA), which, through self-assembling, forms a rigid shell that contains doxorubicin (DOX) and NIF fluorescent dye IR780 on the surface of the perfluorohexane (PFH) microbubbles. The results show that CNC NPs have a hollow core-shell structure with an average particle size of 97.3 ± 27.2 nm and have exceptional colloidal stability and photothermal conversion efficiency. The NPs can effectively perform cascade drug release through ultrasound triggering and pH responding. CNC NPs have good in vivo biological safety and excellent fluorescence imaging, drug delivery, and therapeutic abilities in the TNBC models. These results provide an experimental basis for the development of new clinical treatment methods for TNBC.
    Keywords:  nanocarriers; near-infrared imaging; synergistic therapy; triggered release; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2021.747608
  30. Neurochem Res. 2021 Oct 08.
    Coupling of GABA Metabolism to Mitochondrial Glucose Phosphorylation.
    Joao Paulo Cavalcanti-de-Albuquerque, Eduardo de-Souza-Ferreira, Denise Pires de Carvalho, Antonio Galina.
      Glucose and oxygen (O2) are vital to the brain. Glucose metabolism and mitochondria play a pivotal role in this process, culminating in the increase of reactive O2 species. Hexokinase (HK) is a key enzyme on glucose metabolism and is coupled to the brain mitochondrial redox modulation by recycling ADP for oxidative phosphorylation (OXPHOS). GABA shunt is an alternative pathway to GABA metabolism that increases succinate levels, a Krebs cycle intermediate. Although glucose and GABA metabolisms are intrinsically connected, their interplay coordinating mitochondrial function is poorly understood. Here, we hypothesize that the HK and the GABA shunt interact to control mitochondrial metabolism differently in the cortex and the hypothalamus. The GABA shunt stimulated mitochondrial O2 consumption and H2O2 production higher in hypothalamic synaptosomes (HSy) than cortical synaptosomes (CSy). The GABA shunt increased the HK coupled to OXPHOS activity in both population of synaptosomes, but the rate of activation was higher in HSy than CSy. Significantly, malonate and vigabatrin blocked the effects of the GABA shunt in the HK activity coupled to OXPHOS. It indicates that the glucose phosphorylation is linked to GABA and Krebs cycle reactions. Together, these data shed light on the HK and SDH role on the metabolism of each region fed by GABA turnover, which depends on the neurons' metabolic route.
    Keywords:  Bioenergetics; Brain; GABA shunt; Hexokinase; Mitochondria; Synaptosome
    DOI:  https://doi.org/10.1007/s11064-021-03463-2
  31. Crit Rev Food Sci Nutr. 2021 Oct 04. 1-20
    Recent insights on tea metabolites, their biosynthesis and chemo-preventing effects: A review.
    Ramkumar Samynathan, Muthu Thiruvengadam, Shivraj Hariram Nile, Mohammad Ali Shariati, Maksim Rebezov, Raghvendra Kumar Mishra, Baskar Venkidasamy, Sureshkumar Periyasamy, Ill-Min Chung, Mirian Pateiro, José M Lorenzo.
      Tea manufactured from the cultivated shoots of Camellia sinensis (L.) O. Kuntze is the most commonly consumed nonalcoholic drink around the world. Tea is an agro-based, environmentally sustainable, labor-intensive, job-generating, and export-oriented industry in many countries. Tea includes phenolic compounds, flavonoids, alkaloids, vitamins, enzymes, crude fibers, protein, lipids, and carbohydrates, among other biochemical constituents. This review described the nature of tea metabolites, their biosynthesis and accumulation with response to various factors. The therapeutic application of various metabolites of tea against microbial diseases, cancer, neurological, and other metabolic disorders was also discussed in detail. The seasonal variation, cultivation practices and genetic variability influence tea metabolite synthesis. Tea biochemical constituents, especially polyphenols and its integral part catechin metabolites, are broadly focused on potential applicability for their action against various diseases. In addition to this, tea also contains bioactive flavonoids that possess health-beneficial effects. The catechin fractions, epigallocatechin 3-gallate and epicatechin 3-gallate, are the main components of tea that has strong antioxidant and medicinal properties. The synergistic function of natural tea metabolites with synthetic drugs provides effective protection against various diseases. Furthermore, the application of nanotechnologies enhanced bioavailability, enhancing the therapeutic potential of natural metabolites against numerous diseases and pathogens.
    Keywords:   Camellia sinensis (L.) O. Kuntze; bioactive compounds; catechins; flavonoids; protection; therapeutic potential
    DOI:  https://doi.org/10.1080/10408398.2021.1984871
  32. Endocrine. 2021 Oct 08.
    Obesity, metabolic syndrome, and cancer: pathophysiological and therapeutic associations.
    Nikoletta Mili, Stavroula A Paschou, Dimitrios G Goulis, Meletios-Athanasios Dimopoulos, Irene Lambrinoudaki, Theodora Psaltopoulou.
      Overweight, obesity, and metabolic syndrome (MetS) have become epidemic conditions affecting 39%, 13%, and 20% of the population respectively. The aim of this article is to review the literature on the association of obesity and MetS with the risk of cancer. We also explore the effect of lifestyle modifications, such as diet, physical activity, and antidiabetic medications, on cancer incidence. Increased body mass index (BMI) has been associated with a multitude of site-specific cancers, reaching relative risk (RR) 1.54 [95% confidence interval (CI) 1.47-1.61] per 5 unit increase for endometrial cancer, as well as with overall cancer risk (RR 1.03, 95% CI 1.02-1.05). Central adiposity measured by waist circumference or waist-to-hip ratio has been suggested as a stronger predictor than BMI for several cancers, such as colorectal cancer. Metabolic Syndrome has been consistently and positively associated with the risk of very common cancers like colorectal (RR 1.34, 95% CI 1.24-1.44), endometrial (RR 1.62, 95% CI 1.26-2.07) and postmenopausal breast cancer (RR 2.01, 95% CI 1.55-2.60). Hyperglycemia and subsequently T2DM have been also shown to increase the risk of cancer. Nevertheless, these risk factors are modifiable and therefore implementing lifestyle modifications could prevent an important number of cancer cases. Adherence to cancer prevention guidelines, including maintaining a healthy weight, having regular physical exercise (RR 0.58-0.90 for different cite specific cancers) and following a healthy dietary pattern (RR 0.74-0.94 for different cite specific cancers) have a protective effect on the risk of cancer. The strength of this review is the presentation of the best evidence, as the data derive mainly from meta-analyses. Public health policies should focus on the modification of risk factors and future research is needed to reveal the pathophysiological links between these risk factors and cancer to develop more efficient prevention and treatment strategies.
    Keywords:  Cancer; Diabetes; Metabolic syndrome; Metformin; Obesity
    DOI:  https://doi.org/10.1007/s12020-021-02884-x
  33. Lab Invest. 2021 Oct 08.
    Pharmacological inhibition of serine synthesis enhances temozolomide efficacy by decreasing O6-methylguanine DNA methyltransferase (MGMT) expression and reactive oxygen species (ROS)-mediated DNA damage in glioblastoma.
    Lei Jin, Karrie Mei-Yee Kiang, Stephen Yin Cheng, Gilberto Ka-Kit Leung.
      Glioblastoma (GBM) is the most malignant primary tumor in the central nervous system of adults. Temozolomide (TMZ), an alkylating agent, is the first-line chemotherapeutic agent for GBM patients. However, its efficacy is often limited by innate or acquired chemoresistance. Cancer cells can rewire their metabolic programming to support rapid growth and sustain cell survival against chemotherapies. An example is the de novo serine synthesis pathway (SSP), one of the main branches from glycolysis that is highly activated in multiple cancers in promoting cancer progression and inducing chemotherapy resistance. However, the roles of SSP in TMZ therapy for GBM patients remain unexplored. In this study, we employed NCT503, a highly selective inhibitor of phosphoglycerate dehydrogenase (PHGDH, the first rate-limiting enzyme of SSP), to study whether inhibition of SSP may enhance TMZ efficacy in MGMT-positive GBMs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flowcytometry and colony formation assays demonstrated that NCT503 worked synergistically with TMZ in suppressing GBM cell growth and inducing apoptosis in T98G and U118 cells in vitro. U118 and patient-derived GBM subcutaneous xenograft models showed that combined NCT503 and TMZ treatment inhibited GBM growth and promoted apoptosis more significantly than would each treatment alone in vivo. Mechanistically, we found that NCT503 treatment decreased MGMT expression possibly by modulating the Wnt/β-catenin pathway. Moreover, intracellular levels of reactive oxygen species were elevated especially when NCT503 and TMZ treatments were combined, and the synergistic effects could be partially negated by NAC, a classic scavenger of reactive oxygen species. Taken together, these results suggest that NCT503 may be a promising agent for augmenting TMZ efficacy in the treatment of GBM, especially in TMZ-resistant GBMs with high expression of MGMT.
    DOI:  https://doi.org/10.1038/s41374-021-00666-7
  34. J Oncol. 2021 ;2021 3619510
    Therapeutic Effects of Polyphenols on the Treatment of Colorectal Cancer by Regulating Wnt β-Catenin Signaling Pathway.
    Mehran Pashirzad, Thomas P Johnston, Amirhossein Sahebkar.
      Colorectal cancer (CRC) is the third most common cause of cancer-related death worldwide in terms of both its rates of incidence and mortality. Due to serious side effects associated with conventional chemotherapeutic treatments, many natural products with fewer adverse side effects have been considered as potential treatment options. In fact, many natural products have widely been used in various phases of clinical trials for CRC, as well as in in vitro and in vivo preclinical studies. Curcumin (CUR) and resveratrol (RES) are classified as natural polyphenolic compounds that have been demonstrated to have anticancer activity against CRC and are associated with minimal side effects. By regulating select target genes involved in several key signaling pathways in CRC, in particular, the Wnt β-catenin signaling cascade, the course of CRC may be positively altered. In the current review, we focused on the therapeutic effects of CUR and RES in CRC as they pertain to modulation of the Wnt β-catenin signaling pathway.
    DOI:  https://doi.org/10.1155/2021/3619510
  35. Front Endocrinol (Lausanne). 2021 ;12 732255
    The Effects of Diet and Exercise on Endogenous Estrogens and Subsequent Breast Cancer Risk in Postmenopausal Women.
    Alleigh G Wiggs, Justin K Chandler, Aynur Aktas, Susan J Sumner, Delisha A Stewart.
      Endogenous estrogens have been associated with overall breast cancer risk, particularly for postmenopausal women, and ways to reduce these estrogens have served as a primary means to decrease overall risk. This narrative review of clinical studies details how various nutritional and exercise lifestyle interventions have been used to modify estrogen levels and metabolism to provide a protective impact against breast cancer incidence. We also summarized the evidence supporting the efficacy of interventions, outcomes of interest and identified emerging research themes. A systematic PubMed MEDLINE search identified scholarly articles or reviews published between 2000-2020 that contained either a cohort, cross-sectional, or interventional study design and focused on the relationships between diet and/or exercise and overall levels of different forms of estrogen and breast cancer risk and occurrence. Screening and data extraction was undertaken by two researchers. Data synthesis was narrative due to the heterogeneous nature of studies. A total of 1625 titles/abstracts were screened, 198 full texts reviewed; and 43 met eligibility criteria. Of the 43 studies, 28 were randomized controlled trials, and 15 were observational studies. Overall, studies that incorporated both diet and exercise interventions demonstrated better control of detrimental estrogen forms and levels and thus likely represent the best strategies for preventing breast cancer development for postmenopausal women. Some of the strongest associations included weight loss via diet and diet + exercise interventions, reducing alcohol consumption, and consuming a varied dietary pattern, similar to the Mediterranean diet. More research should be done on the effects of specific nutritional components on endogenous estrogen levels to understand the effect that the components have on their own and in combination within the diet.
    Keywords:  breast cancer prevention; breast cancer risk; diet; estrogen; exercise; metabolism; postmenopasal women
    DOI:  https://doi.org/10.3389/fendo.2021.732255
  36. FEBS J. 2021 Oct 04.
    Respiratory Complex I dysfunction in cancer: from a maze of cellular adaptive responses to potential therapeutic strategies.
    Manuela Sollazzo, Monica De Luise, Silvia Lemma, Licia Bressi, Maria Iorio, Stefano Miglietta, Sara Milioni, Ivana Kurelac, Luisa Iommarini, Giuseppe Gasparre, Anna Maria Porcelli.
      Mitochondria act as key organelles in cellular bioenergetics and biosynthetic processes producing signals that regulate different molecular networks for proliferation and cell death. This ability is also preserved in pathologic contexts such as tumorigenesis, during which bioenergetic changes and metabolic reprogramming confer flexibility favoring cancer cells survival in a hostile microenvironment. Although different studies epitomize mitochondrial dysfunction as a pro-tumorigenic hit, genetic ablation or pharmacological inhibition of respiratory Complex I causing a severe impairment are associated with a low proliferative phenotype. In this scenario, it must be considered that despite the initial delay in growth, cancer cells may become able to resume proliferation exploiting molecular mechanisms to overcome growth arrest. Here we highlight the current knowledge on molecular responses activated by Complex I-defective cancer cells to bypass physiological control systems and to re-adapt their fitness during microenvironment changes. Such adaptive mechanisms could reveal possible novel molecular players in synthetic lethality with Complex I impairment, thus providing new synergistic strategies for mitochondria-based anti-cancer therapy.
    Keywords:  Respiratory complex I; adaptive responses; cancer metabolism; mitochondria; tumor microenvironment
    DOI:  https://doi.org/10.1111/febs.16218
  37. Adv Mater. 2021 Oct 05. e2101572
    Precise Subcellular Organelle Targeting for Boosting Endogenous-Stimuli-Mediated Tumor Therapy.
    Wenyao Zhen, Shangjie An, Shuqi Wang, Wenxue Hu, Yujie Li, Xiue Jiang, Jinghong Li.
      Though numerous external-stimuli-triggered tumor therapies, including phototherapy, radiotherapy, and sonodynamic therapy have made great progress in cancer therapy, the low penetration depth of the laser, safety concerns of radiation, the therapeutic resistance, and the spatio-temporal constraints of the specific equipment restrict their convenient clinical applications. What is more, the inherent physiological barriers of the tumor microenvironment (TME), including hypoxia, heterogeneity, and high expression of antioxidant molecules also restrict the efficiency of tumor therapy. As a result, the development of nanoplatforms responsive to endogenous stimuli (such as glucose, acidic pH, cellular redox events, and etc.) has attracted great attention for starvation therapy, ion therapy, prodrug-mediated chemotherapy, or enzyme-catalyzed therapy. In addition, nanomedicines can be modified by some targeted units for precisely locating in subcellular organelles and boosting the destroying of tumor tissue, decreasing the dosage of nanoagents, reducing side effects, and enhancing the therapeutic efficiency. Herein, the properties of the TME, the advantages of endogenous stimuli, and the principles of subcellular-organelle-targeted strategies will be emphasized. Some necessary considerations for the exploitation of precision medicine and clinical translation of multifunctional nanomedicines in the future are also pointed out.
    Keywords:  cancer therapy; endogenous stimuli; nanomedicine; precise therapy; subcellular organelles; targeting
    DOI:  https://doi.org/10.1002/adma.202101572
  38. Magy Onkol. 2021 Oct 06. 65(3): 201-205
    [Molecular classification of pancreatic cancer].
    József Tímár.
      Pancreatic cancer is a malignancy with outstandingly poor prognosis caused by several factors among which one is that it is predominated by mutant KRAS oncogene. Genomic studies revealed that clinically useful therapy targets are present only in the DNA repair deficient subgroup and in the minor wild type KRAS-carrying group. However, phylogenetic studies defined four molecular subgroups of pancreatic cancer among which the immunogenic progenitor form could well be the target of immunotherapies. Furthermore, this group may well be the one characterized by DNA repair deficiency and high tumor mutational burden. Furthermore, the majority of familiar pancreatic cancers could also be found in this latter subgroup. Unfortunately, the G12C mutation of KRAS in pancreatic cancer is rare, therefore pancreatic cancer patients could not benefit from the recent revolution of KRAS target therapies.
  39. Mol Cell Oncol. 2021 ;8(4): 1927446
    Regulation of glycolysis and cancer cell proliferation by PKM2 citrullination.
    Sébastien Coassolo, Irwin Davidson.
      Conversion of peptidyl-arginine to peptidyl citrulline, known as citrullination, is a post-translational protein modification catalyzed by the PADI (Protein Arginine Deiminase) family of enzymes. PADI1 and PADI3 catalyze citrullination of arginine 106 in the glycolytic enzyme pyruvate kinase M2 modulating its allosteric regulation, glycolysis and cancer cell proliferation.
    Keywords:  NuRD complex; allosteric regulation; chromatin; melanoma; protein arginine deiminase
    DOI:  https://doi.org/10.1080/23723556.2021.1927446
  40. Adv Clin Exp Med. 2021 Oct 05.
    Dualistic role of autophagy in cancer progression.
    Kacper Turek, Michał Jarocki, Julita Kulbacka, Jolanta Saczko.
      This review aims to characterize the dualistic role of autophagy in both the suppression and propagation of carcinogenesis. The process of autophagy is responsible for maintaining the delicate balance between the survival and death of a cell, and in the past years it has been studied profoundly. It has been proven that the role of autophagy in maintaining genomic and structural integrity can lead to the suppression of carcinogenesis in its early stages. However, once carcinogenesis has occurred, the process of autophagy may contribute to the survival of tumor cells and, consequently, lead to tumor progression. Additionally, autophagy can modulate the response of the tumor cells to therapy, leading to radiotherapy and chemotherapy resistance or reduced susceptibility to anticancer drugs that propagate autophagy-related cell death. Although the role and course of autophagy are not yet fully known, the essence of it seems to be within our grasp. We have observed the identification of an increasing number of autophagy-related genes (ATG). Therefore, more research concerning its molecular course and potential applications in cancer treatment and prevention needs to be conducted.
    Keywords:  autophagy; cancer progression; chaperons; oncogenes
    DOI:  https://doi.org/10.17219/acem/141191
  41. Front Bioeng Biotechnol. 2021 ;9 730925
    Synthesis and Photothermal Effects of Intracellular Aggregating Nanodrugs Targeting Nasopharyngeal Carcinoma.
    Ying Zhong, Naveen Kumar Bejjanki, Xiangwan Miao, Huanhuan Weng, Quanming Li, Juan Zhang, Tao Liu, Raghu Vannam, Minqiang Xie.
      Chemotherapy for the treatment of nasopharyngeal carcinoma (NPC) is usually associated with many side effects; therefore, its treatment options have not yet been completely resolved. Improving distribution to the targeted tumor region and enhancing the cellular uptake of drugs can efficiently alleviate the above adverse medical effects. Near-infrared (NIR) laser light-mediated photothermal therapy (PTT) and photodynamic therapy (PDT) are promising strategies for cancer treatment. In the present study, we developed an efficient multifunctional nanocluster with enhanced targeting and aggregation efficiency for PTT and PDT that is composed of a biocompatible folic acid (FA), indocyanine green (ICG) and 2-cyanobenzothiazole (CBT)-functionalized peptide labeled with an aldehyde sodium alginate-modified magnetic iron oxide nanoparticle (ASA-MNP)-based nanocarrier. FA can bind to folate receptors on cancer cell membranes to enhance nanocluster uptake. CBT-modified peptide can react with glutathione (GSH), which is typically present at higher levels in cancer cells, to form intracellular aggregates and increase the local concentration of the nanodrug. In in vitro studies, these nanodrugs displayed the desired uptake capacity by NPC cells and the ability to suppress the growth of cancer cells under laser irradiation. Animal studies validated that these nanodrugs are safe and nontoxic, efficiently accumulate in NPC tumor sites following injection via the caudal vein, and shows superior inhibition of tumor growth in a tumor-bearing mouse model upon near-infrared laser irradiation. The results indicate the potential application of the multifunctional nanoparticles (NPs), which can be used as a new method for the treatment of folate receptor-positive NPC.
    Keywords:  folic acid targeting; indocyanine green; intracellular aggregation; nasopharyngeal carcinoma; photothermal effect
    DOI:  https://doi.org/10.3389/fbioe.2021.730925
  42. Life Sci. 2021 Sep 30. pii: S0024-3205(21)00994-2. [Epub ahead of print] 120007
    Metabolic fasting stress is ameliorated in Kinin B1 receptor-deficient mice.
    Leandro Ceotto Freitas-Lima, Alexandre Budu, Gabriel Rufino Estrela, Thais Alves da Silva, Adriano Cleis Arruda, Ronaldo de Carvalho Araujo.
      The liver has an essential role in responding to metabolic demands under stress conditions. The organ stores, releases, and recycles metabolism-related substrates. However, it is not clear how the Kallikrein-Kinin System modulates metabolic flexibility shift between energetic sources.
    AIMS: To analyze the hepatic metabolism in kinin B1 receptor deficient mice (B1KO mice) under fasting conditions.
    MAIN METHODS: WT and B1KO male mice were allocated in a calorimetric cage for 7 days and 48 h before the euthanasia, half of the animals of both groups were under fasting conditions. Biochemical parameters, ketone bodies (KB), and gene expression involving the liver energetic metabolism genes were evaluated.
    KEY FINDINGS: Kinin B1 receptor (B1R) modulates the metabolic shift under fasting conditions, reducing the VO2 expenditure. A preference for carbohydrates as an energetic source is suggested, as the B1KO group did not display an increase in KB in the serum. Moreover, the B1KO animals displayed higher serum triglycerides concentration compared to WT fasting mice. Interestingly, the lack of B1R induces the increase expression of enzymes from the glycolysis and lipolysis pathways under the fed. However, under fasting, the enzymatic expression of gluconeogenesis, glyceroneogenesis, and ketogenesis of these pathways does not occur, suggesting an absence of the shift metabolism responsivity, and this condition is modulated by PDK4 under FOXO1 control.
    SIGNIFICANCE: B1R has an important role in the hepatic glucose metabolism, which in turn influences the energetic metabolism, and in long-term outcomes, such as in the decrease in hepatic glycogen stores and in the enhancement of hepatic metabolism.
    Keywords:  Fasting; Glucose metabolism; Ketone bodies; Kinin B1 receptor; Metabolic flexibility
    DOI:  https://doi.org/10.1016/j.lfs.2021.120007
  43. Cell Metab. 2021 Sep 30. pii: S1550-4131(21)00423-X. [Epub ahead of print]
    "Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis.
    Mark A Febbraio, Michael Karin.
      Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous. Although dietary fructose was thought to be metabolized exclusively in the liver, evidence has emerged that it is also metabolized in the small intestine and leads to intestinal epithelial barrier deterioration. Along with the clinical manifestations of hereditary fructose intolerance, these findings suggest that, along with the direct effect of fructose on liver metabolism, the gut-liver axis plays a key role in fructose metabolism and pathology. Here, we summarize recent studies on fructose biology and pathology and discuss new opportunities for prevention and treatment of diseases associated with high-fructose consumption.
    Keywords:  NASH; cancer; fructos; gut inflammation; metabolic disease
    DOI:  https://doi.org/10.1016/j.cmet.2021.09.004
  44. Oncotarget. 2021 Sep 28. 12(20): 2104-2110
    Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers.
    Austin R Dosch, Walid K Chatila, Yuguang Ban, Anna Bianchi, Nilesh U Deshpande, Iago De Castro Silva, Nipun B Merchant, Jashodeep Datta.
      Despite increasingly thorough mechanistic understanding of the dominant genetic drivers of gastrointestinal (GI) tumorigenesis (e.g., Ras/Raf, TP53, etc.), only a small proportion of these molecular alterations are therapeutically actionable. In an attempt to address this therapeutic impasse, our group has proposed an innovative extreme outlier model to identify novel cooperative molecular vulnerabilities in high-risk GI cancers which dictate prognosis, correlate with distinct patterns of metastasis, and define therapeutic sensitivity or resistance. Our model also proposes comprehensive investigation of their downstream transcriptomic, immunomic, metabolic, or upstream epigenomic cellular consequences to reveal novel therapeutic targets in previously "undruggable" tumors with high-risk genomic features. Leveraging this methodology, our and others' data reveal that the genomic cooperativity between Ras and p53 alterations is not only prognostically relevant in GI malignancy, but may also represent the incipient molecular events that initiate and sustain innate immunoregulatory signaling networks within the GI tumor microenvironment, driving T-cell exclusion and therapeutic resistance in these cancers. As such, deciphering the unique transcriptional programs encoded by Ras-p53 cooperativity that promote innate immune trafficking and chronic inflammatory tumor-stromal-immune crosstalk may uncover immunologic vulnerabilities that could be exploited to develop novel therapeutic strategies for these difficult-to-treat malignancies.
    Keywords:  Ras; Ras-p53 cooperativity; TP53; gastrointestinal cancer; immune
    DOI:  https://doi.org/10.18632/oncotarget.27983
  45. Drug Deliv. 2021 Dec;28(1): 2108-2118
    Co-delivery of sorafenib and crizotinib encapsulated with polymeric nanoparticles for the treatment of in vivo lung cancer animal model.
    Tian Zhong, Xingren Liu, Hongmin Li, Jing Zhang.
      To treat various cancers, including lung cancer, chemotherapy requires the systematic administering of chemotherapy. The chemotherapeutic effectiveness of anticancer drugs has been enhanced by polymer nanoparticles (NPs), according to new findings. As an outcome, we have developed biodegradable triblock poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) polymeric NPs for the co-delivery of sorafenib (SORA) and crizotinib (CRIZ) and investigated their effect on lung cancer by in vitro and in vivo. There is little polydispersity in the SORA-CRIZ@NPs, an average size of 30.45 ± 2.89 nm range. A steady release of SORA and CRIZ was observed, with no burst impact. The apoptosis rate of SORA-CRIZ@NPs was greater than that of free drugs in 4T1 and A549 cells. Further, in vitro cytotoxicity of the polymeric NPs loaded with potential anticancer drugs was more quickly absorbed by cancer cells. On the other hand, compared to free drugs (SORA + CRIZ), SORA + CRIZ@NPs showed a substantial reduction of tumor development, longer survival rate, and a lowered side effect when delivered intravenously to nude mice xenograft model with 4T1 cancer cells. TUNEL positivity was also increased in tumor cells treated with SORA-CRIZ@NPs, demonstrating the therapeutic effectiveness. SORA-CRIZ@NPs might be used to treat lung cancer soon, based on the results from our new findings.
    Keywords:  Polymeric nanoparticles; apoptosis; co-delivery; in vivo animal model; lung cancer
    DOI:  https://doi.org/10.1080/10717544.2021.1979129
  46. 3 Biotech. 2021 Oct;11(10): 453
    Expanding the bio-catalysis scope and applied perspectives of nanocarrier immobilized asparaginases.
    Hamza Rafeeq, Asim Hussain, Muhammad Haseeb Anwar Tarar, Nadia Afsheen, Muhammad Bilal, Hafiz M N Iqbal.
      l-asparaginase is an essential enzyme in medicine and a well-known chemotherapeutic agent. This enzyme's importance is not limited to its use as an anti-cancer agent; it also has a wide variety of medicinal applications. Antimicrobial properties, prevention of infectious disorders, autoimmune diseases, and canine and feline cancer are among the applications. Apart from the healthcare industry, its importance has been identified in the food industry as a food manufacturing agent to lower acrylamide levels. When isolated from their natural habitats, they are especially susceptible to different denaturing conditions due to their protein composition. The use of an immobilization technique is one of the most common approaches suggested to address these limitations. Immobilization is a technique that involves fixing enzymes to or inside stable supports, resulting in a heterogeneous immobilized enzyme framework. Strong support structures usually stabilize the enzymes' configuration, and their functions are maintained as a result. In recent years, there has been a lot of curiosity and focus on the ability of immobilized enzymes. The nanomaterials with ideal properties can be used to immobilize enzymes to regulate key factors that determine the efficacy of bio-catalysis. With applications in biotechnology, immunosensing, biomedicine, and nanotechnology sectors have opened a realm of opportunities for enzyme immobilization.
    Keywords:  Applications; Asparaginase; Biocatalysis; Immobilization; Nanocarriers
    DOI:  https://doi.org/10.1007/s13205-021-02999-y
  47. Nat Rev Cancer. 2021 Oct 05.
    Evolving cancer-niche interactions and therapeutic targets during bone metastasis.
    Robert L Satcher, Xiang H-F Zhang.
      Many cancer types metastasize to bone. This propensity may be a product of genetic traits of the primary tumour in some cancers. Upon arrival, cancer cells establish interactions with various bone-resident cells during the process of colonization. These interactions, to a large degree, dictate cancer cell fates at multiple steps of the metastatic cascade, from single cells to overt metastases. The bone microenvironment may even influence cancer cells to subsequently spread to multiple other organs. Therefore, it is imperative to spatiotemporally delineate the evolving cancer-bone crosstalk during bone colonization. In this Review, we provide a summary of the bone microenvironment and its impact on bone metastasis. On the basis of the microscopic anatomy, we tentatively define a roadmap of the journey of cancer cells through bone relative to various microenvironment components, including the potential of bone to function as a launch pad for secondary metastasis. Finally, we examine common and distinct features of bone metastasis from various cancer types. Our goal is to stimulate future studies leading to the development of a broader scope of potent therapies.
    DOI:  https://doi.org/10.1038/s41568-021-00406-5
  48. Blood. 2021 Oct 05. pii: blood.2021011563. [Epub ahead of print]
    Proton export alkalinizes intracellular pH and reprograms carbon metabolism to drive hematopoietic progenitor growth.
    Cheuk Him Man, Francois Emile Mercier, Nian Liu, Wentao Dong, Gregory Stephanopoulos, Li Jiang, Yookyung Jung, Charles Lin, Anskar Yh Leung, David T Scadden.
      Proton export is often considered a detoxifying process in animal cells with monocarboxylate symporters co-exporting excessive lactate and protons during glycolysis or the Warburg effect. Here we report a novel mechanism by which lactate/H+ export is sufficient to induce cell growth. Increased lactate/proton export induces intracellular alkalization that selectively activates catalysis by key metabolic gatekeeper enzymes, HK1/PKM2/G6PDH, thereby enhancing glycolytic and pentose phosphate pathway carbon flux. The result is increased nucleotide levels, NADPH/NADP+ ratio and cell proliferation. Simply increasing the lactate/proton symporter, MCT4, or sodium-proton antiporter, NHE1 was sufficient to increase intracellular-pH (pHi) and give normal hematopoietic cells a significant competitive growth advantage in vivo. This process does not require additional cytokine triggers and is exploited in malignancy where leukemogenic mutations epigenetically increase MCT4. Inhibiting MCT4 decreased intracellular pH, carbon flux and eliminated acute myeloid leukemia-initiating-cells without cytotoxic chemotherapy. Intracellular alkalization is a primitive mechanism by which proton partitioning can directly reprogram carbon metabolism for cell growth.
    DOI:  https://doi.org/10.1182/blood.2021011563
  49. Nanoscale. 2021 Oct 08.
    Ultrasound augments on-demand breast tumor radiosensitization and apoptosis through a tri-responsive combinatorial delivery theranostic platform.
    Prateek Bhardwaj, Jayant Sastri Goda, Venkatesh Pai, Pradip Chaudhari, Bhabani Mohanty, Trupti Pai, Komal Vishwakarma, Rahul Thorat, Tabassum Wadasadawala, Rinti Banerjee.
      Advanced inoperable triple-negative breast cancer (TNBC) comprises aggressive tumors with a modest pathological response to neoadjuvant chemotherapy. The concomitant use of chemoradiotherapy improves the pathological response rates. However, the dose-dependent systemic toxicity of clinical radiosensitizers with poor circulation half-life and limited passive bioavailability limits their clinical utility. We address these challenges by rationally designing a stealth and tumor microenvironment responsive nano-conjugate platform for the ultrasound-mediated on-demand spatio-temporal delivery of plant flavonoid curcumin as a combinatorial regimen with clinically approved paclitaxel for the neoadjuvant chemoradiotherapy of locally advanced triple-negative breast cancer (TNBC). Interestingly, the focused application of ultrasound at the orthotopic TNBC xenograft of NOD-SCID mice facilitated the immediate infiltration of nano-conjugates at the tumor interstitium, and conferred in vivo safety over marketed paclitaxel formulation. In addition, curcumin significantly potentiated the in vivo chemoradiotherapeutic efficacy of paclitaxel upon loading into nano-conjugates. This gets further enhanced by the concurrent pulse of ultrasound, as confirmed by PET-CT imaging, along with a significant improvement in the mice survival. The quadrapeutic apoptotic effect by the combination of paclitaxel, curcumin, radiation, and ultrasound, along with a reduction in the tumor microvessel density and cell proliferation marker, confers the broad chemo-radiotherapeutic potential of this regimen for radio-responsive solid tumors, as well as metastatic niches.
    DOI:  https://doi.org/10.1039/d1nr04211d
  50. Mol Syst Biol. 2021 Oct;17(10): e10480
    Multistability maintains redox homeostasis in human cells.
    Jo-Hsi Huang, Hannah Kc Co, Yi-Chen Lee, Chia-Chou Wu, Sheng-Hong Chen.
      Cells metabolize nutrients through a complex metabolic and signaling network that governs redox homeostasis. At the core of this, redox regulatory network is a mutually inhibitory relationship between reduced glutathione and reactive oxygen species (ROS)-two opposing metabolites that are linked to upstream nutrient metabolic pathways (glucose, cysteine, and glutamine) and downstream feedback loops of signaling pathways (calcium and NADPH oxidase). We developed a nutrient-redox model of human cells to understand system-level properties of this network. Combining in silico modeling and ROS measurements in individual cells, we show that ROS dynamics follow a switch-like, all-or-none response upon glucose deprivation at a threshold that is approximately two orders of magnitude lower than its physiological concentration. We also confirm that this ROS switch can be irreversible and exhibits hysteresis, a hallmark of bistability. Our findings evidence that bistability modulates redox homeostasis in human cells and provide a general framework for quantitative investigations of redox regulation in humans.
    Keywords:  bistability; glucose deprivation; redox homeostasis
    DOI:  https://doi.org/10.15252/msb.202110480
  51. Compr Rev Food Sci Food Saf. 2021 Oct 05.
    Acylated anthocyanins: A review on their bioavailability and effects on postprandial carbohydrate metabolism and inflammation.
    Johanna Jokioja, Baoru Yang, Kaisa M Linderborg.
      Anthocyanins, the natural red and purple colorants of berries, fruits, vegetables, and tubers, improve carbohydrate metabolism and decrease the risk factors of metabolic disorders, but their industrial use is limited by their chemical instability. Acylation of the glycosyl moieties of anthocyanins, however, changes the chemical properties of anthocyanins and provides enhanced stability. Thus, acylated anthocyanins are more usable as natural colorants and bioactive components of innovative functional foods. Acylated anthocyanins are common in pigmented vegetables and tubers, the consumption of which has the potential to increase the intake of health-promoting anthocyanins as part of the daily diet. For the first time, this review presents the current findings on bioavailability, absorption, metabolism, and health effects of acylated anthocyanins with comparison to more extensively investigated nonacylated anthocyanins. The structural differences between nonacylated and acylated anthocyanins lead to enhanced color stability, altered absorption, bioavailability, in vivo stability, and colonic degradation. The impact of phenolic metabolites and their potential health effects regardless of the low bioavailability of the parent anthocyanins as such is discussed. Here, purple-fleshed potatoes are presented as a globally available, eco-friendly model food rich in acylated anthocyanins, which further highlights the industrial possibilities and nutritional relevance of acylated anthocyanins. This work supports the academic community and industry in food research and development by reviewing the current literature and highlighting gaps of knowledge.
    Keywords:  acylated anthocyanins; bioavailability; inflammation; nutrition; phenolics; pigments; postprandial carbohydrate metabolism
    DOI:  https://doi.org/10.1111/1541-4337.12836
  52. Small. 2021 Oct 08. e2103919
    Metal-Polyphenol-Network Coated Prussian Blue Nanoparticles for Synergistic Ferroptosis and Apoptosis via Triggered GPX4 Inhibition and Concurrent In Situ Bleomycin Toxification.
    Lulu Zhou, Jinjin Chen, Ruihao Li, Lizhen Wei, Haitao Xiong, Chunhui Wang, Keke Chai, Mengyao Chen, Zhounan Zhu, Tianming Yao, Yun Lin, Chunyan Dong, Shuo Shi.
      Given that traditional anticancer therapies fail to significantly improve the prognoses of triple negative breast cancer (TNBC), new modalities with high efficiency are urgently needed. Herein, by mixing the metal-phenolic network formed by tannic acid (TA), bleomycin (BLM), and Fe3+ with glutathione peroxidase 4 (GPX4) inhibitor (ML210) loaded hollow mesoporous Prussian blue (HMPB) nanocubes, the HMPB/ML210@TA-BLM-Fe3+ (HMTBF) nanocomplex is prepared to favor the ferroptosis/apoptosis synergism in TNBC. During the intracellular degradation, Fe3+ /Fe2+ conversion mediated by TA can initiate the Fenton reaction to drastically upregulate the reactive oxygen species level in cells, subsequently induce the accumulation of lipid peroxidation, and thereby cause ferroptotic cell death; meanwhile, the released ML210 efficiently represses the activity of GPX4 to activate ferroptosis pathway. Besides, the chelation of Fe2+ with BLM leads to in situ BLM toxification at tumor site, then triggers an effective apoptosis to synergize with ferroptosis for tumor therapy. As a result, the superior in vivo antitumor efficacy of HMTBF is corroborated in a 4T1 tumor-bearing mice model regarding tumor growth suppression, indicating that the nanoformulations can serve as efficient ferroptosis and apoptosis inducers for use in combinatorial TNBC therapy.
    Keywords:  GPX4 inhibition; Prussian blue; ferroptosis; in situ toxification; synergistic tumor therapy
    DOI:  https://doi.org/10.1002/smll.202103919
  53. Biomed Pharmacother. 2021 Oct 05. pii: S0753-3322(21)01061-1. [Epub ahead of print]144 112277
    Mechanisms of induction of tumors by cholesterol and potential therapeutic prospects.
    Yang Xi, Zhou Yani, Mao Jing, Wu Yinhang, Hou Xiaohui, Zhuang Jing, Qi Quan, Han Shuwen.
      Increasing evidence suggested that cholesterol is an important integrant of cell membranes, that plays a key role in tumor progression, immune dysregulation, and pathological changes in epigenetic mechanisms. Based on these theories, there is a growing interest on targeting cholesterol in the treatment of cancer. Here, we comprehensively reviewed the major function of cholesterol on oncogenicity, the therapeutic targets of cholesterol and its metabolites in cancer, and provide detailed insight into the essential roles of cholesterol in mediating immune and epigenetic mechanisms of the tumor microenvironment. It is also worth mentioning that the gut microbiome is an indispensable component of cancer mediation because of its role in cholesterol metabolism. Finally, we summarized recent studies on the potential targets of cholesterol and their metabolism, to provide more therapeutic interventions in oncology.
    Keywords:  Cholesterol; Epigenetic; Gut microbiome; Immune; Metabolites
    DOI:  https://doi.org/10.1016/j.biopha.2021.112277
  54. Front Pharmacol. 2021 ;12 746385
    Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer.
    Md Sazzad Hassan, Nicholas Cwidak, Chloe Johnson, Silvio Däster, Serenella Eppenberger-Castori, Niranjan Awasthi, Jun Li, Margaret A Schwarz, Urs von Holzen.
      Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.
    Keywords:  BMS-754807; c-Myc; esophageal cancer; flavopiridol; nanoparticle albumin-bound paclitaxel
    DOI:  https://doi.org/10.3389/fphar.2021.746385
  55. J Control Release. 2021 Oct 01. pii: S0168-3659(21)00528-9. [Epub ahead of print]
    Multifunctional nanoreactors-integrated microneedles for cascade reaction-enhanced cancer therapy.
    Yixian Zhou, Boyi Niu, Yiting Zhao, Jintao Fu, Ting Wen, Kaixin Liao, Guilan Quan, Xin Pan, Chuanbin Wu.
      Starvation therapy based on glucose oxidase (GOx) has attracted considerable attention in tumor treatment. However, several shortcomings severely hinder its further applications, including limited therapeutic efficacy, poor enzyme stability, and potential side effects. Herein, a strategy of cascade reaction-enhanced combined therapy based on the oxygen-evolving multifunctional nanoreactors is proposed for tumor therapy. The GOx and catalase (CAT) are immobilized in metal-organic frameworks by biomimetic mineralization to improve their stability via spatial confinement. The GOx can consume glucose, reduce ATP levels, and down-regulate the expression of heat shock proteins, which consequently sensitize tumor cells to indocyanine green-based photothermal therapy. Furthermore, the hydrogen peroxide generated by GOx as well as overexpressed in tumor can be decomposed by CAT and continuously generate oxygen, which further enhance the efficacy of oxygen-dependent starvation therapy and photodynamic therapy. The nanoreactors are directly delivered to the superficial tumor by microneedles, achieving efficient tumor accumulation and dramatically strengthened antitumor efficacy without obvious side effects, which provides a valuable paradigm for the application of cascade reaction-based combined therapy.
    Keywords:  Cancer therapy; Cascade reaction; Glucose oxidase; Microneedles; Oxygen supply
    DOI:  https://doi.org/10.1016/j.jconrel.2021.09.041
  56. J Adv Res. 2021 Nov;33 201-213
    Innate tumor-targeted nanozyme overcoming tumor hypoxia for cancer theranostic use.
    Hanitrarimalala Veroniaina, Zhenghong Wu, Xiaole Qi.
       Introduction: Hypoxic tumor microenvironment (TME) is the major contributor to cancer metastasis, resistance to chemotherapy, and recurrence of tumors. So far, no approved treatment has been available to overcome tumor hypoxia.
    Objectives: The present study aimed to relieve tumor hypoxia via a nanozyme theranostic nanomaterial as well as providing magnetic resonance imaging (MRI)-guided therapy.
    Methods: Manganese dioxide (MnO2) was used for its intrinsic enzymatic activity co-loaded with the anti-cancer drug Doxorubicin (Dox) within the recombinant heavy-chain apoferritin cavity to form MnO2-Dox@HFn. Following the synthesis of the nanomaterial, different characterizations were performed as well as its nanozyme-like ability. This nanoplatform recognizes tumor cells through the transferrin receptors 1 (TfR1) which are highly expressed on the surface of most cancer cells. The cellular uptake was confirmed by flow cytometry and fluorescence spectroscopy. In vitro and in vivo studies have been investigated to evaluate the hypoxia regulation, MRI ability and anti-tumor activity of MnO2-Dox@HFn.
    Results: Being a TME-responsive nanomaterial, MnO2-Dox@HFn exerted both peroxidase and catalase activity that mainly produce massive oxygen and Mn2+ ions. Respectively, these products relieve the unfavorable tumor hypoxia and also exhibit T1-weighted MRI with a high longitudinal relaxivity of 33.40 mM. s-1. The utility of MnO2-Dox@HFn was broadened with their efficient anti-cancer activity proved both in vitro and in vivo.
    Conclusions: MnO2-Dox@HFn successfully overcome tumor hypoxia with double potentials enzymatic ability and diagnostic capacity. This investigation could ignite the future application for cancer theranostic nanozyme therapy.
    Keywords:  Apoferritin; Cancer theranostic; Manganese dioxide; Nanozyme; Tumor hypoxia
    DOI:  https://doi.org/10.1016/j.jare.2021.02.004
  57. Pharmacol Ther. 2021 Oct 05. pii: S0163-7258(21)00215-1. [Epub ahead of print] 108013
    Polyphenols and neuroprotection: Therapeutic implications for cognitive decline.
    Giuseppe Caruso, Sebastiano Alfio Torrisi, Paola Mogavero, Walter Currenti, Sabrina Castellano, Justyna Godos, Raffaele Ferri, Fabio Galvano, Gian Marco Leggio, Giuseppe Grosso, Filippo Caraci.
      Dietary polyphenols have been the focus of major interest for their potential benefits on human health. Several preclinical studies have been conducted to provide a rationale for their potential use as therapeutic agents in preventing or ameliorating cognitive decline. However, results from human studies are scarce and poorly documented. The aim of this review was to discuss the potential mechanisms involved in age-related cognitive decline or early stage cognitive impairment and current evidence from clinical human studies conducted on polyphenols and the aforementioned outcomes. The evidence published so far is encouraging but contrasting findings are to be taken into account. Most studies on anthocyanins showed a consistent positive effect on various cognitive aspects related to aging or early stages of cognitive impairment. Studies on cocoa flavanols, resveratrol, and isoflavones provided substantial contrasting results and further research is needed to clarify the therapeutic potential of these compounds. Results from other studies on quercetin, green tea flavanols, hydroxycinnamic acids (such as chlorogenic acid), curcumin, and olive oil tyrosol and derivatives are rather promising but still too few to provide any real conclusions. Future translational studies are needed to address issues related to dosage, optimal formulations to improve bioavailability, as well as better control for the overall diet, and correct target population.
    Keywords:  Anthocyanins; Catechins; Cognitive decline; Cognitive impairment; Nutraceuticals; Polyphenols; Resveratrol; chlorogenic acid; isoflavones; quercetin
    DOI:  https://doi.org/10.1016/j.pharmthera.2021.108013
  58. Clin Transl Oncol. 2021 Oct 05.
    Inhibitory effect of polyphenols (phenolic acids, lignans, and stilbenes) on cancer by regulating signal transduction pathways: a review.
    A Hazafa, M O Iqbal, U Javaid, M B K Tareen, D Amna, A Ramzan, S Piracha, M Naeem.
      Natural products, especially polyphenols (phenolic acids, lignans, and stilbenes) are suggested to be more potent anticancer drugs because of their no or less adverse effects, excess availability, high accuracy, and secure mode of action. In the present review, potential anticancer mechanisms of action of some polyphenols including phenolic acids, lignans, and stilbenes are discussed based on clinical, epidemiological, in vivo, and in vitro studies. The emerging evidence revealed that phenolic acids, lignans, and stilbenes induced apoptosis in the treatment of breast (MCF-7), colon (Caco-2), lung (SKLU-1), prostate (DU-145 and LNCaP), hepatocellular (hepG-2), and cervical (A-431) cancer cells, cell cycle arrest (S/G2/M/G1-phases) in gastric (MKN-45 and MKN-74), colorectal (HCT-116), bladder (T-24 and 5637), oral (H-400), leukemic (HL-60 and MOLT-4) and colon (Caco-2) cancer cells, and inhibit cell proliferation against the prostate (PC-3), liver (LI-90), breast (T47D and MDA-MB-231), colon (HT-29 and Caco-2), cervical (HTB-35), and MIC-1 cancer cells through caspase-3, MAPK, AMPK, Akt, NF-κB, Wnt, CD95, and SIRT1 pathways. Based on accumulated data, we suggested that polyphenols could be considered as a viable therapeutic option in the treatment of cancer cells in the near future.
    Keywords:  Apoptosis; Cancer; Cell cycle arrest; Natural compounds; Phenolic acids; Resveratrol
    DOI:  https://doi.org/10.1007/s12094-021-02709-3
  59. Phytomedicine. 2021 Sep 16. pii: S0944-7113(21)00299-3. [Epub ahead of print] 153756
    Sophoridine: A review of its pharmacology, pharmacokinetics and toxicity.
    Qi Wang, Ying Li, Kun-Wei Li, Chang-Zheng Zhou.
       BACKGROUND: Sophoridine is a bioactive alkaloid found in many Chinese herbs, such as Sophora alopecuroides l, Euchresta japonica Benth and Sophora moocrorftinan. Sophoridine hydrochloride injection has been approved as an anticancer drug in China.
    PURPOSE: This review aims to provide a comprehensive summary on the pharmacological, molecular mechanism, pharmacokinetic and toxicity studies of sophoridine.
    METHOD: PubMed, Web of Science and China National Knowledge Infrastructure were used for a systematic search with the keywords including "sophoridine", "pharmacology", "pharmacokinetics", and "toxicity".
    RESULTS: Emerging evidence suggests that sophoridine exhibits a broad spectrum of pharmacological activities including antitumor, anti-inflammatory, antiviral, myocardialprotective and hepatoprotective activities. These pharmacological properties lay foundation for using the plants containing sophoridine for the treatment of numerous diseases, such as cancer, colitis, injury of lungs, ischemia myocardial,etc. The mechanisms involved in the pharmacological actions of sophoridine are regulation of NF-κB, TLR4/IRF3, JNK/ERK, Akt/mTOR signaling pathways, down-regulating the expression of HMG3B, bcl-2, MMP-2, MMP-9, TNF-α, IL-1β IL-6 and other cytokines or kinases. However, an increasing number of published reports indicated that sophoridine has serious adverse effects. The primary toxic effects are neurotoxicity and acute toxicity, which are of wide concern in worldwide. Moreover, sophoridine is reported to distribute in kidney, liver, uterus, lung and other organs. It undergoes glucuronidation and excreted in urine.
    CONCLUSION: Future studies should elucidate the detailed in vivo metabolism studies on sophoridine. The effect of substituent functional groups on sophoridine on metabolism, the enzymes involved in the metabolism and the chemistry of metabolites also should be studied. Either structural modification of sophoridine or its combined with other drugs may play a pivotal role to enhance its pharmacological activities and reduce its toxicity.
    Keywords:  Pharmacokinetics; Pharmacology; Sophoridine; Toxicology
    DOI:  https://doi.org/10.1016/j.phymed.2021.153756
  60. Nat Rev Endocrinol. 2021 Oct 04.
    Multifaceted actions of melanin-concentrating hormone on mammalian energy homeostasis.
    Omar Al-Massadi, Carlos Dieguez, Marc Schneeberger, Miguel López, Markus Schwaninger, Vincent Prevot, Ruben Nogueiras.
      Melanin-concentrating hormone (MCH) is a small cyclic peptide expressed in all mammals, mainly in the hypothalamus. MCH acts as a robust integrator of several physiological functions and has crucial roles in the regulation of sleep-wake rhythms, feeding behaviour and metabolism. MCH signalling has a very broad endocrine context and is involved in physiological functions and emotional states associated with metabolism, such as reproduction, anxiety, depression, sleep and circadian rhythms. MCH mediates its functions through two receptors (MCHR1 and MCHR2), of which only MCHR1 is common to all mammals. Owing to the wide variety of MCH downstream signalling pathways, MCHR1 agonists and antagonists have great potential as tools for the directed management of energy balance disorders and associated metabolic complications, and translational strategies using these compounds hold promise for the development of novel treatments for obesity. This Review provides an overview of the numerous roles of MCH in energy and glucose homeostasis, as well as in regulation of the mesolimbic dopaminergic circuits that encode the hedonic component of food intake.
    DOI:  https://doi.org/10.1038/s41574-021-00559-1
  61. Front Mol Biosci. 2021 ;8 741316
    Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents.
    Vinodh Kannappan, Misha Ali, Benjamin Small, Gowtham Rajendran, Salena Elzhenni, Hamza Taj, Weiguang Wang, Q Ping Dou.
      Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.
    Keywords:  cancer; cancer stem cells; copper; diethyldithiocarbamate; disulfiram; disulfiram copper complex; drug repurposing; drug-delivery-system
    DOI:  https://doi.org/10.3389/fmolb.2021.741316
  62. J Mater Chem B. 2021 Oct 05.
    Gas and gas-generating nanoplatforms in cancer therapy.
    Yuan-Zhe Jing, Shu-Jin Li, Zhi-Jun Sun.
      Gas therapy is the usage of certain gases with special therapeutic effects for the treatment of diseases. Hydrogen (H2), nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) acting as gas signalling molecules are representative gases in cancer therapy. They act directly on mitochondria or nuclei to lead to cell apoptosis. They can also alleviate immuno-suppression in the tumour microenvironment and promote phenotype conversion of tumour-associated macrophages. Moreover, the combination of gas therapy and other traditional therapy methods can reduce side effects and improve therapeutic efficacy. Here, we discuss the roles of NO, CO, H2S and H2 in cancer biology. Considering the rapidly developing nanotechnology, gas-generating nanoplatforms which can achieve targeted delivery and controlled release were also discussed. Finally, we highlight the current challenges and future opportunities of gas-based cancer therapy.
    DOI:  https://doi.org/10.1039/d1tb01661j
  63. Cell Death Dis. 2021 Oct 05. 12(10): 909
    Autophagy provides a conceptual therapeutic framework for bone metastasis from prostate cancer.
    YouZhi Wang, Ning Wu, Ning Jiang.
      Prostate cancer is a common malignant tumor, which can spread to multiple organs in the body. Metastatic disease is the dominant reason of death for patients with prostate cancer. Prostate cancer usually transfers to bone. Bone metastases are related to pathologic fracture, pain, and reduced survival. There are many known targets for prostate cancer treatment, including androgen receptor (AR) axis, but drug resistance and metastasis eventually develop in advanced disease, suggesting the necessity to better understand the resistance mechanisms and consider multi-target medical treatment. Because of the limitations of approved treatments, further research into other potential targets is necessary. Metastasis is an important marker of cancer development, involving numerous factors, such as AKT, EMT, ECM, tumor angiogenesis, the development of inflammatory tumor microenvironment, and defect in programmed cell death. In tumor metastasis, programmed cell death (autophagy, apoptosis, and necroptosis) plays a key role. Malignant cancer cells have to overcome the different forms of cell death to transfer. The article sums up the recent studies on the mechanism of bone metastasis involving key regulatory factors such as macrophages and AKT and further discusses as to how regulating autophagy is crucial in relieving prostate cancer bone metastasis.
    DOI:  https://doi.org/10.1038/s41419-021-04181-x
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