bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–10–24
95 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer.
  2. Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers.
  3. MicroRNAs and Metabolism: Revisiting the Warburg Effect with Emphasis on Epigenetic Background and Clinical Applications.
  4. VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges.
  5. Lactate in the tumour microenvironment: From immune modulation to therapy.
  6. Diet comparison suggests a lipid imbalance can slow tumour growth.
  7. Methylosystem for Cancer Sieging Strategy.
  8. Multi‑faceted role of cancer‑associated adipocytes in the tumor microenvironment (Review).
  9. A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment.
  10. Ketogenic Diet for Cancer: Critical Assessment and Research Recommendations.
  11. Latest Innovations and Nanotechnologies with Curcumin as a Nature-Inspired Photosensitizer Applied in the Photodynamic Therapy of Cancer.
  12. Tryptophan and its metabolites in normal physiology and cancer etiology.
  13. The Intersection of Purine and Mitochondrial Metabolism in Cancer.
  14. Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters.
  15. STAT3 Mediated Regulation of Glucose Metabolism in Leukemia Cells.
  16. Immunomodulatory Effects of Tryptophan Metabolism in the Glioma Tumor Microenvironment.
  17. Hypoxically cultured cells of oral squamous cell carcinoma increased their glucose metabolic activity under normoxic conditions.
  18. Low glycaemic diets alter lipid metabolism to influence tumour growth.
  19. Metabolic reprogramming in cervical cancer and metabolomics perspectives.
  20. Interplay between Epigenetics and Cellular Metabolism in Colorectal Cancer.
  21. Tumor-suppressive function of EZH2 is through inhibiting glutaminase.
  22. Molecular Targets and Promising Therapeutics of Triple-Negative Breast Cancer.
  23. Bruceae Fructus Oil Inhibits Triple-Negative Breast Cancer by Restraining Autophagy: Dependence on the Gut Microbiota-Mediated Amino Acid Regulation.
  24. NeuroD1 promotes tumor cell proliferation and tumorigenesis by directly activating the pentose phosphate pathway in colorectal carcinoma.
  25. Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells.
  26. ERK: A Double-Edged Sword in Cancer. ERK-Dependent Apoptosis as a Potential Therapeutic Strategy for Cancer.
  27. KRAS Mutant Combination Therapy for the Effective Treatment of Cancer.
  28. Evaluation of KRAS Concomitant Mutations in Advanced Lung Adenocarcinoma Patients.
  29. Cancer-Associated Fibroblast Functions as a Road-Block in Cancer Therapy.
  30. Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities.
  31. Cancer associated fibroblast subpopulations with diverse and dynamic roles in the tumor microenvironment.
  32. Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH.
  33. MCT1 expression is independently related to shorter cancer-specific survival in clear cell renal cell carcinoma.
  34. Metabolomics Based on 1H-NMR Reveal the Regulatory Mechanisms of Dietary Methionine Restriction on Splenic Metabolic Dysfunction in Obese Mice.
  35. Iron-Regulated Reactive Oxygen Species Production and Programmed Cell Death in Chronic Obstructive Pulmonary Disease.
  36. Redox Homeostasis and Regulation in Pluripotent Stem Cells: Uniqueness or Versatility?
  37. Development of a KRAS-Associated Metabolic Risk Model for Prognostic Prediction in Pancreatic Cancer.
  38. Potentiality of Nanoenzymes for Cancer Treatment and Other Diseases: Current Status and Future Challenges.
  39. 5-Aminolevulinic Acid Triggered by Ultrasound Halts Tumor Proliferation in a Syngeneic Model of Breast Cancer.
  40. Calcineurin inactivation inhibits pyruvate dehydrogenase complex activity and induces the Warburg effect.
  41. Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis.
  42. Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution.
  43. Lactate as an Astroglial Signal Augmenting Aerobic Glycolysis and Lipid Metabolism.
  44. Phytochemicals from Indian Ethnomedicines: Promising Prospects for the Management of Oxidative Stress and Cancer.
  45. CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity.
  46. DIRAS3: An Imprinted tumor suppressor gene that regulates RAS and PI3K-driven cancer growth, motility, autophagy and tumor dormancy.
  47. Preclinical and Clinical Antioxidant Effects of Natural Compounds against Oxidative Stress-Induced Epigenetic Instability in Tumor Cells.
  48. Combinative treatment of Curdione and docetaxel triggers reactive oxygen species (ROS)-mediated intrinsic apoptosis of triple-negative breast cancer cells.
  49. Repurposing drugs as novel triple negative breast cancer therapeutics.
  50. Time-Restricted Eating: A Novel and Simple Dietary Intervention for Primary and Secondary Prevention of Breast Cancer and Cardiovascular Disease.
  51. Capsaicin exerts therapeutic effects by targeting tNOX-SIRT1 axis and augmenting ROS-dependent autophagy in melanoma cancer cells.
  52. Pharmacometabolomics by NMR in Oncology: A Systematic Review.
  53. Loss of the wild-type KRAS allele promotes pancreatic cancer progression through functional activation of YAP1.
  54. The metabolic roots of senescence: mechanisms and opportunities for intervention.
  55. Metabolic Tumor Microenvironment Characterization of Contrast Enhancing Brain Tumors Using Physiologic MRI.
  56. The Interplay Between Prostate Cancer Genomics, Metabolism, and the Epigenome: Perspectives and Future Prospects.
  57. A Key Silencing Histone Mark on Chromatin Is Lost When Colorectal Adenocarcinoma Cells Are Depleted of Methionine by Methionine γ-Lyase.
  58. Dual Inhibition of KRAS G12C and G12D Mutants as a Potential Treatment in Cancer Therapy.
  59. PDGFRβ Modulates Aerobic Glycolysis in Osteosarcoma HOS Cells via the PI3K/AKT/mTOR/c-Myc Pathway.
  60. Influence of Dietary Compounds on Arsenic Metabolism and Toxicity. Part II-Human Studies.
  61. Screening compound libraries for H2O2-mediated cancer therapeutics using a peroxiredoxin-based sensor.
  62. Advances in Hyaluronic acid-based (nano)devices for Cancer Therapy.
  63. Could Photodynamic Therapy Be a Promising Therapeutic Modality in Hepatocellular Carcinoma Patients? A Critical Review of Experimental and Clinical Studies.
  64. Nanosonosensitizers With Ultrasound-Induced Reactive Oxygen Species Generation for Cancer Sonodynamic Immunotherapy.
  65. After decades, RAS mutation has finally become a therapeutic target.
  66. Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment.
  67. The impact of nutrition and lifestyle modification on health.
  68. Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression.
  69. Targeting the Redox Balance Pathway Using Ascorbic Acid in sdhb Zebrafish Mutant Larvae.
  70. Protocatechuic Acid, a Simple Plant Secondary Metabolite, Induced Apoptosis by Promoting Oxidative Stress through HO-1 Downregulation and p21 Upregulation in Colon Cancer Cells.
  71. Redox Control of the Dormant Cancer Cell Life Cycle.
  72. Chrysin induces autophagy-dependent ferroptosis to increase chemosensitivity to gemcitabine by targeting CBR1 in pancreatic cancer cells.
  73. Biomedical Applications of Chinese Herb-Synthesized Silver Nanoparticles by Phytonanotechnology.
  74. Modulation of KRAS Mutant by Inhibiting PLK1 Kinase in Cancer Therapeutics.
  75. Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells.
  76. Functional Proteomic Profiling of Triple-Negative Breast Cancer.
  77. Developing Actively Targeted Nanoparticles to Fight Cancer: Focus on Italian Research.
  78. Hyperhomocysteinemia: Metabolic Role and Animal Studies with a Focus on Cognitive Performance and Decline-A Review.
  79. The Multifaceted Therapeutic Mechanisms of Curcumin in Osteosarcoma: State-of-the-Art.
  80. Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab.
  81. Anthocyanins in Colorectal Cancer Prevention Review.
  82. Fasting and Exercise in Oncology: Potential Synergism of Combined Interventions.
  83. Bio-nanoparticle based therapeutic vaccine induces immunogenic response against triple negative breast cancer.
  84. Myoglobin Protects Breast Cancer Cells Due to Its ROS and NO Scavenging Properties.
  85. Tumor Microenvironment Modulating Functional Nanoparticles for Effective Cancer Treatments.
  86. Improving Curcumin Bioavailability: Current Strategies and Future Perspectives.
  87. Small molecule-mediated induction of endoplasmic reticulum stress in cancer cells.
  88. Selenium-Catalyzed Reduction of Hydroperoxides in Chemistry and Biology.
  89. Host-cell-assisted construction of a folate-engineered nanocarrier based on viral light particles for targeted cancer therapy.
  90. Targeted Delivery and Site-Specific Activation of β-Cyclodextrin-Conjugated Photosensitizers for Photodynamic Therapy through a Supramolecular Bio-orthogonal Approach.
  91. Neutrophils in cancer carcinogenesis and metastasis.
  92. Antitumoral Activities of Curcumin and Recent Advances to ImProve Its Oral Bioavailability.
  93. Prolonged cortisol elevation alters whole body and tissue metabolism in rainbow trout (Oncorhynchus mykiss).
  94. Influence of Dietary Compounds on Arsenic Metabolism and Toxicity. Part I-Animal Model Studies.
  95. Dormancy in the Tumor Microenvironment.
  1. Cancers (Basel). 2021 Oct 19. pii: 5250. [Epub ahead of print]13(20):
    Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer.
    Chaofan Fan, Shing Kam, Pierluigi Ramadori.
      Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.
    Keywords:  SAM; Warburg effect; acetyl-CoA; combinatorial therapy; guadecitabine; immunometabolism; liver cancer; metformin; resminostat
    DOI:  https://doi.org/10.3390/cancers13205250
  2. Cancers (Basel). 2021 Oct 11. pii: 5081. [Epub ahead of print]13(20):
    Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers.
    Yuta Adachi, Ryo Kimura, Kentaro Hirade, Hiromichi Ebi.
      Activating mutations in KRAS are present in 25% of human cancers. When mutated, the KRAS protein becomes constitutively active, stimulating various effector pathways and leading to the deregulation of key cellular processes, including the suppression of apoptosis and enhancement of proliferation. Furthermore, mutant KRAS also promotes metabolic deregulation and alterations in the tumor microenvironment. However, some KRAS mutant cancer cells become independent of KRAS for their survival by activating diverse bypass networks that maintain essential survival signaling originally governed by mutant KRAS. The proposed inducers of KRAS independency are the activation of YAP1 and/or RSK-mTOR pathways and co-mutations in SKT11 (LKB1), KEAP1, and NFE2L2 (NRF2) genes. Metabolic reprogramming, such as increased glutaminolysis, is also associated with KRAS autonomy. The presence or absence of KRAS dependency is related to the heterogeneity of KRAS mutant cancers. Epithelial-to-mesenchymal transition (EMT) in tumor cells is also a characteristic phenotype of KRAS independency. Translationally, this loss of dependence is a cause of primary and acquired resistance to mutant KRAS-specific inhibitors. While KRAS-dependent tumors can be treated with mutant KRAS inhibitor monotherapy, for KRAS-independent tumors, we need an improved understanding of activated bypass signaling pathways towards leveraging vulnerabilities, and advancing therapeutic options for this patient subset.
    Keywords:  EMT; KRAS; RSK; YAP1; autonomy; dependency; metabolic reprogramming
    DOI:  https://doi.org/10.3390/cancers13205081
  3. Biomolecules. 2021 Oct 17. pii: 1531. [Epub ahead of print]11(10):
    MicroRNAs and Metabolism: Revisiting the Warburg Effect with Emphasis on Epigenetic Background and Clinical Applications.
    Zsuzsanna Gaál.
      Since the well-known hallmarks of cancer were described by Hanahan and Weinberg, fundamental advances of molecular genomic technologies resulted in the discovery of novel puzzle pieces in the multistep pathogenesis of cancer. MicroRNAs are involved in the altered epigenetic pattern and metabolic phenotype of malignantly transformed cells. They contribute to the initiation, progression and metastasis-formation of cancers, also interacting with oncogenes, tumor-suppressor genes and epigenetic modifiers. Metabolic reprogramming of cancer cells results from the dysregulation of a complex network, in which microRNAs are located at central hubs. MicroRNAs regulate the expression of several metabolic enzymes, including tumor-specific isoforms. Therefore, they have a direct impact on the levels of metabolites, also influencing epigenetic pattern due to the metabolite cofactors of chromatin modifiers. Targets of microRNAs include numerous epigenetic enzymes, such as sirtuins, which are key regulators of cellular metabolic homeostasis. A better understanding of reversible epigenetic and metabolic alterations opened up new horizons in the personalized treatment of cancer. MicroRNA expression levels can be utilized in differential diagnosis, prognosis stratification and prediction of chemoresistance. The therapeutic modulation of microRNA levels is an area of particular interest that provides a promising tool for restoring altered metabolism of cancer cells.
    Keywords:  Warburg effect; cancer epigenetics; metabolism; microRNAs; personalized treatment
    DOI:  https://doi.org/10.3390/biom11101531
  4. Front Physiol. 2021 ;12 742839
    VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges.
    Kareem A Heslop, Veronica Milesi, Eduardo N Maldonado.
      Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.
    Keywords:  Warburg; cancer; glycolysis; metabolic flexibility; metabolic reprogramming; metabolism; mitochondria; voltage dependent anion channels
    DOI:  https://doi.org/10.3389/fphys.2021.742839
  5. EBioMedicine. 2021 Oct 13. pii: S2352-3964(21)00420-5. [Epub ahead of print]73 103627
    Lactate in the tumour microenvironment: From immune modulation to therapy.
    Zi-Hao Wang, Wen-Bei Peng, Pei Zhang, Xiang-Ping Yang, Qiong Zhou.
      Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity.
    Keywords:  Cancer immunity; Cancer metabolism; Glycolytic enzymes; Lactate; Monocarboxylate transporters; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.ebiom.2021.103627
  6. Nature. 2021 Oct 20.
    Diet comparison suggests a lipid imbalance can slow tumour growth.
    Giulia Salvadori, Valter D Longo.
      
    Keywords:  Cancer; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-021-02775-1
  7. Cancers (Basel). 2021 Oct 12. pii: 5088. [Epub ahead of print]13(20):
    Methylosystem for Cancer Sieging Strategy.
    Shotaro Tatekawa, Ken Ofusa, Ryota Chijimatsu, Andrea Vecchione, Keisuke Tamari, Kazuhiko Ogawa, Hideshi Ishii.
      As cancer is a genetic disease, methylation defines a biologically malignant phenotype of cancer in the association of one-carbon metabolism-dependent S-adenosylmethionine (SAM) as a methyl donor in each cell. Methylated substances are involved in intracellular metabolism, but via intercellular communication, some of these can also be secreted to affect other substances. Although metabolic analysis at the single-cell level remains challenging, studying the "methylosystem" (i.e., the intercellular and intracellular communications of upstream regulatory factors and/or downstream effectors that affect the epigenetic mechanism involving the transfer of a methyl group from SAM onto the specific positions of nucleotides or other metabolites in the tumor microenvironment) and tracking these metabolic products are important research tasks for understanding spatial heterogeneity. Here, we discuss and highlight the involvement of RNA and nicotinamide, recently emerged targets, in SAM-producing one-carbon metabolism in cancer cells, cancer-associated fibroblasts, and immune cells. Their significance and implications will contribute to the discovery of efficient methods for the diagnosis of and therapeutic approaches to human cancer.
    Keywords:  RNA; cancer-associated fibroblasts; methylation; nicotinamide; one-carbon metabolism
    DOI:  https://doi.org/10.3390/cancers13205088
  8. Mol Med Rep. 2021 Dec;pii: 866. [Epub ahead of print]24(6):
    Multi‑faceted role of cancer‑associated adipocytes in the tumor microenvironment (Review).
    Huihui Yao, Songbing He.
      Adipocytes are a type of stromal cell found in numerous different tissues that serve an active role in the tumor microenvironment. Cancer‑associated adipocytes (CAAs) display a malignant phenotype and are found at the invasive tumor front, which mediates the crosstalk network between adipocytes (the precursor cells that will become cancer‑associated adipocytes in the future) and cancer cells. The present review covers the mechanisms of adipocytes in the development of cancer, including metabolic reprogramming, chemotherapy resistance and adipokine regulation. Furthermore, the potential mechanisms involved in the adipocyte‑cancer cell cycle in various types of cancer, including breast, ovarian, colon and rectal cancer, are discussed. Deciphering the complex network of CAA‑cancer cell crosstalk will provide insights into tumor biology and optimize therapeutic strategies.
    Keywords:  CAA; TME; adipokines; chemotherapy resistance; metabolic reprogramming
    DOI:  https://doi.org/10.3892/mmr.2021.12506
  9. Cells. 2021 Oct 09. pii: 2700. [Epub ahead of print]10(10):
    A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment.
    Francesca Hofer, Gianna Di Sario, Chiara Musiu, Silvia Sartoris, Francesco De Sanctis, Stefano Ugel.
      Myeloid-derived suppressor cells (MDSCs) constitute a plastic and heterogeneous cell population among immune cells within the tumour microenvironment (TME) that support cancer progression and resistance to therapy. During tumour progression, cancer cells modify their metabolism to sustain an increased energy demand to cope with uncontrolled cell proliferation and differentiation. This metabolic reprogramming of cancer establishes competition for nutrients between tumour cells and leukocytes and most importantly, among tumour-infiltrating immune cells. Thus, MDSCs that have emerged as one of the most decisive immune regulators of TME exhibit an increase in glycolysis and fatty acid metabolism and also an upregulation of enzymes that catabolise essential metabolites. This complex metabolic network is not only crucial for MDSC survival and accumulation in the TME but also for enhancing immunosuppressive functions toward immune effectors. In this review, we discuss recent progress in the field of MDSC-associated metabolic pathways that could facilitate therapeutic targeting of these cells during cancer progression.
    Keywords:  cancer; immunometabolism; inflammation; myeloid-derived suppressor cells (MDSC); tumour-microenvironment (TME)
    DOI:  https://doi.org/10.3390/cells10102700
  10. Nutrients. 2021 Oct 12. pii: 3562. [Epub ahead of print]13(10):
    Ketogenic Diet for Cancer: Critical Assessment and Research Recommendations.
    Jordin Lane, Nashira I Brown, Shanquela Williams, Eric P Plaisance, Kevin R Fontaine.
      Despite remarkable improvements in screening, diagnosis, and targeted therapies, cancer remains the second leading cause of death in the United States. It is increasingly clear that diet and lifestyle practices play a substantial role in cancer development and progression. As such, various dietary compositions have been proposed for reducing cancer risk and as potential adjuvant therapies. In this article, we critically assess the preclinical and human trials on the effects of the ketogenic diet (KD, i.e., high-fat, moderate-to-low protein, and very-low carbohydrate content) for cancer-related outcomes. The mechanisms underlying the hypothesized effects of KD, most notably the Warburg Effect, suggest that restricting carbohydrate content may impede cancer development and progression via several pathways (e.g., tumor metabolism, gene expression). Overall, although preclinical studies suggest that KD has antitumor effects, prolongs survival, and prevents cancer development, human clinical trials are equivocal. Because of the lack of high-quality clinical trials, the effects of KD on cancer and as an adjunctive therapy are essentially unknown. We propose a set of research recommendations for clinical studies examining the effects of KD on cancer development and progression.
    Keywords:  adjuvant therapy; cancer; ketogenic
    DOI:  https://doi.org/10.3390/nu13103562
  11. Pharmaceutics. 2021 Sep 26. pii: 1562. [Epub ahead of print]13(10):
    Latest Innovations and Nanotechnologies with Curcumin as a Nature-Inspired Photosensitizer Applied in the Photodynamic Therapy of Cancer.
    Laura Marinela Ailioaie, Constantin Ailioaie, Gerhard Litscher.
      In the context of the high incidence of cancer worldwide, state-of-the-art photodynamic therapy (PDT) has entered as a usual protocol of attempting to eradicate cancer as a minimally invasive procedure, along with pharmacological resources and radiation therapy. The photosensitizer (PS) excited at certain wavelengths of the applied light source, in the presence of oxygen releases several free radicals and various oxidation products with high cytotoxic potential, which will lead to cell death in irradiated cancerous tissues. Current research focuses on the potential of natural products as a superior generation of photosensitizers, which through the latest nanotechnologies target tumors better, are less toxic to neighboring tissues, but at the same time, have improved light absorption for the more aggressive and widespread forms of cancer. Curcumin incorporated into nanotechnologies has a higher intracellular absorption, a higher targeting rate, increased toxicity to tumor cells, accelerates the activity of caspases and DNA cleavage, decreases the mitochondrial activity of cancer cells, decreases their viability and proliferation, decreases angiogenesis, and finally induces apoptosis. It reduces the size of the primary tumor, reverses multidrug resistance in chemotherapy and decreases resistance to radiation therapy in neoplasms. Current research has shown that the use of PDT and nanoformulations of curcumin has a modulating effect on ROS generation, so light or laser irradiation will lead to excessive ROS growth, while nanocurcumin will reduce the activation of ROS-producing enzymes or will determine the quick removal of ROS, seemingly opposite but synergistic phenomena by inducing neoplasm apoptosis, but at the same time, accelerating the repair of nearby tissue. The latest curcumin nanoformulations have a huge potential to optimize PDT, to overcome major side effects, resistance to chemotherapy, relapses and metastases. All the studies reviewed and presented revealed great potential for the applicability of nanoformulations of curcumin and PDT in cancer therapy.
    Keywords:  cancer; curcumin; light; malignant tumors; nanomedicine; natural photosensitizer; photobiomodulation (PBM); photodynamic therapy (PDT)
    DOI:  https://doi.org/10.3390/pharmaceutics13101562
  12. FEBS J. 2021 Oct 22.
    Tryptophan and its metabolites in normal physiology and cancer etiology.
    Lizbeth Perez-Castro, Roy Garcia, Niranjan Venkateswaran, Spencer Barnes, Maralice Conacci-Sorrell.
      Within the growing field of amino acid metabolism, tryptophan (Trp) catabolism is an area of increasing interest. Trp is essential for protein synthesis, and its metabolism gives rise to biologically active catabolites including serotonin and numerous metabolites in the kynurenine (Kyn) pathway. In normal tissues, the production of Trp metabolites is directly regulated by the tissue-specific expression of Trp-metabolizing enzymes. Alterations of these enzymes in cancers can shift the balance and lead to an increased production of specific byproducts that can function as oncometabolites. For example, increased expression of the enzyme IDO1, which converts Trp into Kyn, leads to an increase in Kyn levels in numerous cancers. Kyn functions as an oncometabolite in cancer cells by promoting the activity of the transcription factor aryl hydrocarbon receptor (AHR), which regulates pro-growth genes. Moreover, Kyn also inhibits T cell activity and thus allows cancer cells to evade clearance by the immune system. Therefore, targeting the Kyn pathway has become a therapeutic focus as a novel means to abrogate tumor growth and immune resistance. This review summarizes the biological role and regulation of Trp metabolism and its catabolites with an emphasis on tumor cell growth and immune evasion, and outlines areas for future research focus.
    Keywords:  AHR; IDO1; TDO2; cancer; immune evasion; kynurenine; proliferation; tryptophan
    DOI:  https://doi.org/10.1111/febs.16245
  13. Cells. 2021 Sep 30. pii: 2603. [Epub ahead of print]10(10):
    The Intersection of Purine and Mitochondrial Metabolism in Cancer.
    Humberto De Vitto, Danushka B Arachchige, Brian C Richardson, Jarrod B French.
      Nucleotides are essential to cell growth and survival, providing cells with building blocks for DNA and RNA, energy carriers, and cofactors. Mitochondria have a critical role in the production of intracellular ATP and participate in the generation of intermediates necessary for biosynthesis of macromolecules such as purines and pyrimidines. In this review, we highlight the role of purine and mitochondrial metabolism in cancer and how their intersection influences cancer progression, especially in ovarian cancer. Additionally, we address the importance of metabolic rewiring in cancer and how the evolving landscape of purine synthesis and mitochondria inhibitors can be potentially exploited for cancer treatment.
    Keywords:  amino acids; cancers; metabolic reprogramming; mitochondrial metabolism; purines
    DOI:  https://doi.org/10.3390/cells10102603
  14. Biology (Basel). 2021 Oct 04. pii: 1000. [Epub ahead of print]10(10):
    Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters.
    Frédéric Bouillaud, Noureddine Hammad, Laurent Schwartz.
      Cellular bioenergetics requires an intense ATP turnover that is increased further by hypermetabolic states caused by cancer growth or inflammation. Both are associated with metabolic alterations and, notably, enhancement of the Warburg effect (also known as aerobic glycolysis) of poor efficiency with regard to glucose consumption when compared to mitochondrial respiration. Therefore, beside this efficiency issue, other properties of these two pathways should be considered to explain this paradox: (1) biosynthesis, for this only indirect effect should be considered, since lactate release competes with biosynthetic pathways in the use of glucose; (2) ATP production, although inefficient, glycolysis shows other advantages when compared to mitochondrial respiration and lactate release may therefore reflect that the glycolytic flux is higher than required to feed mitochondria with pyruvate and glycolytic NADH; (3) Oxygen supply becomes critical under hypermetabolic conditions, and the ATP/O2 ratio quantifies the efficiency of oxygen use to regenerate ATP, although aerobic metabolism remains intense the participation of anaerobic metabolisms (lactic fermentation or succinate generation) could greatly increase ATP/O2 ratio; (4) time and space constraints would explain that anaerobic metabolism is required while the general metabolism appears oxidative; and (5) active repression of respiration by glycolytic intermediates, which could ensure optimization of glucose and oxygen use.
    Keywords:  ATP; cancer; energy metabolism; glycolysis; inflammation; lactic fermentation; mitochondria
    DOI:  https://doi.org/10.3390/biology10101000
  15. Gene. 2021 Oct 13. pii: S0378-1119(21)00607-7. [Epub ahead of print] 146012
    STAT3 Mediated Regulation of Glucose Metabolism in Leukemia Cells.
    Burcu Yucel, Sedef Altundağ Kara, Mustafa Baki Cekmen, Saniye Ada, Berna Demırcan Tan.
      Cancer cells rewire metabolic pathways as they demand more ATP and building blocks for proliferation. Glucose is the most consumed nutrient by cancer cells and metabolized to lactate even in the presence of oxygen. This phenomenon is called 'aerobic glycolysis'. Also, glucose level is found lower in tumor environment. Leukemia is characterized by abnormal proliferation of hematopoietic cells. STAT3 a transcription factor and an oncogene is upregulated in many tumor types. Despite its well-defined functions, STAT3 has also been proposed as a metabolic regulator. In this study, we aimed to determine the role STAT3 activation in glucose limitation, in leukemia cell lines. K562, NB-4 and HL-60 cells were found sensitive to glucose limitation. In low glucose conditions, total and nuclear STAT3 protein was decreased in all cells. In mitochondria, S727 phosphorylated STAT3 (mitochondrial form) was determined slightly increased in K562 and NB-4 cells. On the other side, ectopically STAT3 expressing cells had increased glucose consumption and less proliferated in low glucose medium. This data suggests that aerobic glycolysis might be upregulated upon STAT3 expression in leukemia cells, in glucose limitation. Furthermore, in this study, it was found that GLUT3 expressing cells did not reduce STAT3 expression in low glucose medium. GLUT3 was previously determined as a molecular marker for cell sensitivity to glucose limitation, therefore, it could be hypothesized as GLUT3 expressing cells might not need to alter STAT3 expression in low glucose level. Overall, our data suggest that leukemia cells rewire glucose metabolism via STAT3 expression in glucose limitation. Elucidating pathways that cause differential phosphorylation of STAT3 and its interaction with other energy regulating pathways in cellular response to glucose limitation might be beneficial to design new drug targets such as STAT3 inhibitors for leukemia treatment.
    Keywords:  GLUT3; Leukemia; STAT3 pS727; STAT3 pY705; glucose metabolism
    DOI:  https://doi.org/10.1016/j.gene.2021.146012
  16. Front Immunol. 2021 ;12 730289
    Immunomodulatory Effects of Tryptophan Metabolism in the Glioma Tumor Microenvironment.
    Yang Xu, Huikai Zhang, Qian Sun, Rongxin Geng, Fanen Yuan, Baohui Liu, Qianxue Chen.
      Gliomas are the most common primary malignant tumor in adults' central nervous system. While current research on glioma treatment is advancing rapidly, there is still no breakthrough in long-term treatment. Abnormalities in the immune regulatory mechanism in the tumor microenvironment are essential to tumor cell survival. The alteration of amino acid metabolism is considered a sign of tumor cells, significantly impacting tumor cells and immune regulation mechanisms in the tumor microenvironment. Despite the fact that the metabolism of tryptophan in tumors is currently discussed in the literature, we herein focused on reviewing the immune regulation of tryptophan metabolism in the tumor microenvironment of gliomas and analyzed possible immune targets. The objective is to identify potential targets for the treatment of glioma and improve the efficiency of immunotherapy.
    Keywords:  glioma; immunomodulation; metabolism; tryptophan; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2021.730289
  17. PLoS One. 2021 ;16(10): e0254966
    Hypoxically cultured cells of oral squamous cell carcinoma increased their glucose metabolic activity under normoxic conditions.
    Yuta Shinohara, Jumpei Washio, Yuri Kobayashi, Yuki Abiko, Keiichi Sasaki, Nobuhiro Takahashi.
       OBJECTIVE: The oxygen concentration within cancer tissue is known to be low, but is expected to increase rapidly when oxygen is supplied by angiogenesis and hematogenous metastasis, suggesting that rapid increases in oxygen levels might influence cancer cell physiology. Therefore, we investigated the effects of oxygen concentration fluctuations on the glucose metabolism of cancer cells.
    METHODS: The glucose metabolism of oral squamous cell carcinoma (HSC-2 and HSC-3) and normal epithelial (HaCaT) cells cultured under normoxic (21% oxygen) or hypoxic (1% oxygen) conditions was measured using a pH-stat system under normoxic or hypoxic conditions. The acidic end-products and reactive oxygen species (ROS) generated by glucose metabolism were also measured.
    RESULTS: Under normoxic conditions, the metabolic activity of hypoxically cultured cancer cells was significantly increased, and the production of acids other than lactate was upregulated, while the normal cells did not respond to rapid increases in oxygen levels. ROS production was higher in normoxic conditions in all cells, especially the hypoxically cultured HSC-3 cells.
    CONCLUSIONS: Rapid increases in oxygen levels might enhance the glucose metabolism of hypoxically cultured cancer cells by mainly activating the TCA cycle and electron transport system, which might activate cancer cells through the ATP and ROS generation.
    DOI:  https://doi.org/10.1371/journal.pone.0254966
  18. Nature. 2021 Oct 20.
    Low glycaemic diets alter lipid metabolism to influence tumour growth.
    Evan C Lien, Anna M Westermark, Yin Zhang, Chen Yuan, Zhaoqi Li, Allison N Lau, Kiera M Sapp, Brian M Wolpin, Matthew G Vander Heiden.
      Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth1-5. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels6-8, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth.
    DOI:  https://doi.org/10.1038/s41586-021-04049-2
  19. Nutr Metab (Lond). 2021 Oct 19. 18(1): 93
    Metabolic reprogramming in cervical cancer and metabolomics perspectives.
    Boning Li, Long Sui.
      Cumulative studies have shown that metabolic reprogramming is a hallmark of malignant tumors. The emergence of technological advances, such as omics studies, has strongly contributed to the knowledge of cancer metabolism. Cervical cancer is among the most common cancers in women worldwide. Because cervical cancer is a virus-associated cancer and can exist in a precancerous state for years, investigations targeting the metabolic phenotypes of cervical cancer will enhance our understanding of the interference of viruses on host cells and the progression of cervical carcinogenesis. The purpose of this review was to illustrate metabolic perturbations in cervical cancer, the role that human papillomavirus (HPV) plays in remodeling cervical cell metabolism and recent approaches toward application of metabolomics in cervical disease research. Cervical cancer displays typical cancer metabolic profiles, including glycolytic switching, high lactate levels, lipid accumulation and abnormal kynurenine/tryptophan levels. HPV, at least in part, contributes to these alterations. Furthermore, emerging metabolomics data provide global information on the metabolic traits of cervical diseases and may aid in the discovery of biomarkers for diagnosis and therapy.
    Keywords:  Cervical cancer; HPV; Metabolomics; Warburg effect; p53
    DOI:  https://doi.org/10.1186/s12986-021-00615-7
  20. Biomolecules. 2021 Sep 25. pii: 1406. [Epub ahead of print]11(10):
    Interplay between Epigenetics and Cellular Metabolism in Colorectal Cancer.
    Xiaolin Zhang, Zhen Dong, Hongjuan Cui.
      Cellular metabolism alterations have been recognized as one of the most predominant hallmarks of colorectal cancers (CRCs). It is precisely regulated by many oncogenic signaling pathways in all kinds of regulatory levels, including transcriptional, post-transcriptional, translational and post-translational levels. Among these regulatory factors, epigenetics play an essential role in the modulation of cellular metabolism. On the one hand, epigenetics can regulate cellular metabolism via directly controlling the transcription of genes encoding metabolic enzymes of transporters. On the other hand, epigenetics can regulate major transcriptional factors and signaling pathways that control the transcription of genes encoding metabolic enzymes or transporters, or affecting the translation, activation, stabilization, or translocation of metabolic enzymes or transporters. Interestingly, epigenetics can also be controlled by cellular metabolism. Metabolites not only directly influence epigenetic processes, but also affect the activity of epigenetic enzymes. Actually, both cellular metabolism pathways and epigenetic processes are controlled by enzymes. They are highly intertwined and are essential for oncogenesis and tumor development of CRCs. Therefore, they are potential therapeutic targets for the treatment of CRCs. In recent years, both epigenetic and metabolism inhibitors are studied for clinical use to treat CRCs. In this review, we depict the interplay between epigenetics and cellular metabolism in CRCs and summarize the underlying molecular mechanisms and their potential applications for clinical therapy.
    Keywords:  cellular metabolism; colorectal cancer; epigenetics; targeted therapy; tumorigenesis
    DOI:  https://doi.org/10.3390/biom11101406
  21. Cell Death Dis. 2021 Oct 20. 12(11): 975
    Tumor-suppressive function of EZH2 is through inhibiting glutaminase.
    Yongfeng Liu, Cheng-E Tu, Xuxue Guo, Changjie Wu, Chuncai Gu, Qiuhua Lai, Yuxin Fang, Junqi Huang, Zhizhang Wang, Aimin Li, Side Liu.
      Tumors can use metabolic reprogramming to survive nutrient stress. Epigenetic regulators play a critical role in metabolic adaptation. Here we screened a sgRNA library to identify epigenetic regulators responsible for the vulnerability of colorectal cancer (CRC) cells to glucose deprivation and found that more EZH2-knockout cells survived glucose deprivation. Then, we showed that EZH2 expression was significantly downregulated in response to glucose deprivation in a glucose-sensitive CRC cell line, and EZH2-knockdown cells were more resistant to glucose deprivation. Mechanistically, EZH2 deficiency upregulated the expression of glutaminase (GLS) and promoted the production of glutamate, which in turn led to increased synthesis of intracellular glutathione (GSH) and eventually attenuated the reactive oxygen species (ROS)-mediated cell death induced by glucose deprivation. Although EZH2 functioned as an oncogene in cancer progression and EZH2 knockout abolished colorectal cancer development in a mouse model, here we revealed a mechanistic link between EZH2 and metabolic reprogramming via the direct regulation of GLS expression and observed a negative correlation between EZH2 and GLS expression in colorectal cancer tissues. These findings further confirmed the importance of heterogeneity, provided an explanation for the clinical tolerance of cancer cells to EZH2 inhibitors from the perspective of metabolism, and proposed the possibility of combining EZH2 inhibitors and glutamine metabolism inhibitors for the treatment of cancer.
    DOI:  https://doi.org/10.1038/s41419-021-04212-7
  22. Pharmaceuticals (Basel). 2021 Sep 30. pii: 1008. [Epub ahead of print]14(10):
    Molecular Targets and Promising Therapeutics of Triple-Negative Breast Cancer.
    Won-Ji Ryu, Joo Hyuk Sohn.
      Triple-negative breast cancer (TNBC) is one of the most heterogeneous diseases in solid tumors and has limited therapeutic options. Due to the lack of appropriate targetable markers, the mainstay therapeutic strategy for patients with TNBC has been chemotherapy for the last several decades. Indeed, TNBC tumors have no expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 (HER2); therefore, they do not respond to hormone therapy and HER2-targeted therapy. In this review paper, the molecular heterogeneities, possible therapeutic targets, and recently approved and upcoming drugs for TNBC will be summarized.
    Keywords:  heterogeneity; molecular target; new drugs; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/ph14101008
  23. Front Pharmacol. 2021 ;12 727082
    Bruceae Fructus Oil Inhibits Triple-Negative Breast Cancer by Restraining Autophagy: Dependence on the Gut Microbiota-Mediated Amino Acid Regulation.
    Jiyan Su, Xiaohong Chen, Yuanjie Xiao, Dan Li, Muxia Li, Hongfu Li, Jiangjian Huang, Zhengquan Lai, Ziren Su, Yizhen Xie, Dajiang Zhu, Qianjun Chen, Hai Lu, Jingjin He, Chenglai Xia.
      Triple-negative breast cancer (TNBC) has been acknowledged as an aggressive disease with worst prognosis, which requires endeavor to develop novel therapeutic agents. Bruceae fructus oil (BO), a vegetable oil derived from the fruit of Brucea javanica (L.) Merr., is an approved marketable drug for the treatment of cancer in China for several decades. Despite that the anti-breast cancer activity of several quassinoids derived from B. javanica has been found, it was the first time that the potential of BO against TNBC was revealed. Although BO had no cytotoxicity on TNBC cell lines in vitro, the oral administration of BO exhibited a gut microbiota-dependent tumor suppression without toxicity on the non-targeted organs in vivo. By metagenomics and untargeted metabolomics, it was found that BO not only altered the composition and amino acid metabolism function of gut microbiota but also regulated the host's amino acid profile, which was in accordance with the metabolism alternation in gut microbiota. Moreover, the activity of mTOR in tumor was promoted by BO treatment as indicated by the phosphorylation of 4E-binding protein 1 (4E-BP1) and ribosomal protein S6, and hyper-autophagy was consequently restrained. By contrast, the failure of tumor suppression by BO under pseudo germ-free (PGF) condition came with indistinctive changes in autophagy and mTOR activity, implying the critical role of the gut microbiota in BO's anticancer activity. The present study highlighted a promising application of BO against breast cancer with novel efficacy and safety.
    Keywords:  Bruceae fructus oil; amino acid metabolism; autophagy; gut microbiota; mTOR; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fphar.2021.727082
  24. Oncogene. 2021 Oct 16.
    NeuroD1 promotes tumor cell proliferation and tumorigenesis by directly activating the pentose phosphate pathway in colorectal carcinoma.
    Zhuolin Li, Yuxin He, Yanjun Li, Juan Li, Hezhao Zhao, Guanbing Song, Makoto Miyagishi, Shourong Wu, Vivi Kasim.
      Tumor metabolic reprogramming ensures that cancerous cells obtain sufficient building blocks, energy, and antioxidants to sustain rapid growth and for coping with oxidative stress. Neurogenic differentiation factor 1 (NeuroD1) is upregulated in various types of tumors; however, its involvement in tumor cell metabolic reprogramming remains unclear. In this study, we report that NeuroD1 is positively correlated with glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP), in colorectal cancer cells. In addition, the regulation of G6PD by NeuroD1 alters tumor cell metabolism by stimulating the PPP, leading to enhanced production of nucleotides and NADPH. These, in turn, promote DNA and lipid biosynthesis in tumor cells, while decreasing intracellular levels of reactive oxygen species. Mechanistically, we showed that NeuroD1 binds directly to the G6PD promoter to activate G6PD transcription. Consequently, tumor cell proliferation and colony formation are enhanced, leading to increased tumorigenic potential in vitro and in vivo. These findings reveal a novel function of NeuroD1 as a regulator of G6PD, whereby its oncogenic activity is linked to tumor cell metabolic reprogramming and regulation of the PPP. Furthermore, NeuroD1 represents a potential target for metabolism-based anti-tumor therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41388-021-02063-2
  25. Cancers (Basel). 2021 Oct 09. pii: 5058. [Epub ahead of print]13(20):
    Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells.
    Marcella Bonanomi, Noemi Salmistraro, Giulia Fiscon, Federica Conte, Paola Paci, Valentina Bravatà, Giusi Irma Forte, Tatiana Volpari, Manuela Scorza, Fabrizia Mastroianni, Stefano D'Errico, Elenio Avolio, Gennaro Piccialli, Anna Maria Colangelo, Marco Vanoni, Daniela Gaglio, Lilia Alberghina.
      Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.
    Keywords:  CtBP2; cancer metabolic rewiring; epigenetics; metabolomics integration; transcriptomics
    DOI:  https://doi.org/10.3390/cancers13205058
  26. Cells. 2021 Sep 22. pii: 2509. [Epub ahead of print]10(10):
    ERK: A Double-Edged Sword in Cancer. ERK-Dependent Apoptosis as a Potential Therapeutic Strategy for Cancer.
    Reiko Sugiura, Ryosuke Satoh, Teruaki Takasaki.
      The RAF/MEK/ERK signaling pathway regulates diverse cellular processes as exemplified by cell proliferation, differentiation, motility, and survival. Activation of ERK1/2 generally promotes cell proliferation, and its deregulated activity is a hallmark of many cancers. Therefore, components and regulators of the ERK pathway are considered potential therapeutic targets for cancer, and inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic. Notably, ERK1/2 kinases also have pro-apoptotic functions under certain conditions and enhanced ERK1/2 signaling can cause tumor cell death. Although the repertoire of the compounds which mediate ERK activation and apoptosis is expanding, and various anti-cancer compounds induce ERK activation while exerting their anti-proliferative effects, the mechanisms underlying ERK1/2-mediated cell death are still vague. Recent studies highlight the importance of dual-specificity phosphatases (DUSPs) in determining the pro- versus anti-apoptotic function of ERK in cancer. In this review, we will summarize the recent major findings in understanding the role of ERK in apoptosis, focusing on the major compounds mediating ERK-dependent apoptosis. Studies that further define the molecular targets of these compounds relevant to cell death will be essential to harnessing these compounds for developing effective cancer treatments.
    Keywords:  ACA-28; DUSP/MKP; RAS/RAF/MEK/ERK signaling; apoptosis; cancer treatment
    DOI:  https://doi.org/10.3390/cells10102509
  27. ACS Med Chem Lett. 2021 Oct 14. 12(10): 1517-1518
    KRAS Mutant Combination Therapy for the Effective Treatment of Cancer.
    Robert B Kargbo.
      
    DOI:  https://doi.org/10.1021/acsmedchemlett.1c00466
  28. Medicina (Kaunas). 2021 Sep 29. pii: 1039. [Epub ahead of print]57(10):
    Evaluation of KRAS Concomitant Mutations in Advanced Lung Adenocarcinoma Patients.
    Veronica Aran, Mariano Zalis, Tatiane Montella, Carlos Augusto Moreira de Sousa, Bruno L Ferrari, Carlos Gil Ferreira.
      Background and Objectives: One of the most frequently mutated oncogenes in cancer belongs to the Ras family of proto-oncogenes, which encode distinct key signaling events. RAS gain-of-function mutations are present in ~30% of all human cancers, with KRAS being the most frequently mutated isoform showing alterations in different cancer types including lung cancer. This study aimed to investigate the incidence of KRAS mutations, and concomitant mutations, in advanced non-small cell lung adenocarcinoma patients. Materials and Methods: This was a retrospective study, where genomic DNA extracted from paraffin-embedded tumor tissues from 121 Brazilian advanced non-small cell lung adenocarcinoma patients were analyzed to evaluate via Next Generation Sequencing (NGS) the incidence of KRAS mutations and co-occurring mutations and correlate, when possible, to clinicopathological characteristics. Statistical analyses were performed to calculate the prevalence of mutations and to investigate the association between mutational status, mutation type, and sex. Results: The results showed a prevalence of male (N = 63; 54.8%) compared to female patients (N = 52, 45.2%), and mutant KRAS was present in 20.86% (24/115) of all samples. Interestingly, 33.3% of the mutant KRAS samples showed other mutations simultaneously. Conclusions: This study revealed the presence of rare KRAS concomitant mutations in advanced lung adenocarcinoma patients. Further investigation on the importance of these genomic alterations in patient prognosis and treatment response is warranted.
    Keywords:  KRAS; NGS; advanced lung adenocarcinoma; concomitant mutations
    DOI:  https://doi.org/10.3390/medicina57101039
  29. Cancers (Basel). 2021 Oct 19. pii: 5246. [Epub ahead of print]13(20):
    Cancer-Associated Fibroblast Functions as a Road-Block in Cancer Therapy.
    Pradip De, Jennifer Aske, Nandini Dey.
      The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all components of TME in an established solid tumor. We briefly overview the origin, activation, markers, and overall functions of CAF with a particular reference to how different functions of CAF in an established tumor are functionally connected to the development of resistance to cancer therapy in solid tumors. We interrogate the role of CAF in mediating resistance to different modes of therapies. Functional diversity of CAF in orchestrating treatment resistance in solid tumors portrays CAF as a common orchestrator of treatment resistance; a roadblock in cancer therapy.
    Keywords:  cancer therapy; cancer-associated fibroblasts; extracellular matrix; immune cells; stress; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13205246
  30. Cancers (Basel). 2021 Oct 09. pii: 5037. [Epub ahead of print]13(20):
    Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities.
    Maria Alba Sorolla, Ivan Hidalgo, Anabel Sorolla, Robert Montal, Ona Pallisé, Antonieta Salud, Eva Parisi.
      Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, malignant cells modify their habitat, corrupting or transforming cells of different origins and creating the tumor microenvironment (TME). Cells forming the TME like macrophages, neutrophils, and fibroblasts generate reactive oxygen species (ROS) that modify the cancer niche. The effects of ROS in cancer are very diverse: they promote cellular proliferation, epithelial-to-mesenchymal transition (EMT), evasion of cell death programs, migration, and angiogenesis. Due to the multifaceted role of ROS in cancer cell survival and function, ROS-modulating agents such as antioxidants or pro-oxidants could have therapeutic potential in cancer prevention and/or as a complement to systemic treatments. In this review, we will examine the main ROS producer cells and their effects on cancer progression and metastasis. Furthermore, we will enumerate the latest clinical trials where pro-oxidants and antioxidants have therapeutic uses in CRC.
    Keywords:  antioxidants; clinical trials; colorectal cancer; pro-oxidants; reactive oxygen species; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13205037
  31. Mol Cancer Res. 2021 Oct 20. pii: molcanres.0282.2021. [Epub ahead of print]
    Cancer associated fibroblast subpopulations with diverse and dynamic roles in the tumor microenvironment.
    Thomas Simon, Bodour Salhia.
      Close interactions between cancer cells and cancer associated fibroblasts (CAFs) have repeatedly been reported to support tumor progression. Yet, targeting CAFs has so far failed to show a real benefit in cancer treatment, as preclinical studies shown that such strategy can enhance tumor growth. Accordingly, recent paradigm-shifting data suggest that certain CAF subpopulations could also show tumor inhibitory capabilities. The present review aims to provide an in-depth description of the cellular heterogeneity of the CAF compartment in tumors. Through combining information from different cancer types, here we define 4 main CAF subpopulations that might cohabitate in any tumor microenvironment (TME). In addition, a model for the evolution of CAFs during tumor development is introduced. Moreover, the presence of tumor inhibitory CAFs in the TME as well as their molecular characteristics are extensively discussed. Finally, the potential cellular origins of these distinct CAF subpopulations are reviewed. To our knowledge, this is the first attempt at establishing a broad but comprehensive classification of CAF subpopulations. Altogether, the present manuscript aims to provide with the latest developments and innovative insights that could help refine therapeutic targeting of CAFs for cancer treatment.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0282
  32. Pharmaceuticals (Basel). 2021 Oct 19. pii: 1060. [Epub ahead of print]14(10):
    Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH.
    Kyoung Song, Nirmal Rajasekaran, Chaithanya Chelakkot, Hun Seok Lee, Seung-Mann Paek, Hobin Yang, Lina Jia, Hee Geon Park, Woo Sung Son, Yu-Jin Kim, Joon-Seok Choi, Hae Min Jeong, Young-Ger Suh, Hwayoung Yun, Young Kee Shin.
      Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.
    Keywords:  ALDOA; ENO1; FH; Warburg effect; macrosphelide A
    DOI:  https://doi.org/10.3390/ph14101060
  33. Carcinogenesis. 2021 Oct 20. pii: bgab100. [Epub ahead of print]
    MCT1 expression is independently related to shorter cancer-specific survival in clear cell renal cell carcinoma.
    Paulo Afonso de Carvalho, Murilo Bonatelli, Maurício Dener Cordeiro, Rafael Ferreira Coelho, Sabrina Reis, Miguel Srougi, Willian Carlos Nahas, Celine Pinheiro, Katia Ramos Moreira Leite.
      Clear cell renal cell carcinoma (ccRCC) has been considered a metabolic disease, with loss of von Hippel-Lindau (VHL) gene and consequent overexpression of hypoxia-inducible factor 1 alpha (HIF-1α), which is central for tumor development and progression. Among other effects, HIF-1α is involved in the metabolic reprogramming of cancer cells towards the Warburg effect involved in tumor cell proliferation, migration and survival. In this context, several proteins are expressed by cancer cells, including glucose and lactate transporters as well as different pH regulators. Among them, monocarboxylate transporters (MCTs) can be highlighted. Our aim is to comprehensively analyze the immunoexpression of MCT1, MCT2, MCT4, CD147, CD44, HIF-1α, GLUT1 and CAIX in ccRCC surgical specimens correlating with classical prognostic factors and survival of patients with long follow up. Surgical specimens from 207 patients with ccRCC who underwent radical or partial nephrectomy were used to build a tissue microarray. Immunostaining was categorized into absent/weak or moderate/strong and related to all classic ccRCC prognostic parameters. Kaplan-Meier curves were generated to assess overall and cancer-specific survival, and multivariate analysis was performed to identify independent prognostic factors of survival. Multivariate analysis showed that MCT1 together with tumor size and TNM staging, were independently related to cancer-specific survival. MCT1, CD147, CD44 and GLUT1 expression were significantly associated with poor prognostic factors. We show that MCT1 is an independent prognostic factor for cancer-specific survival in ccRCC justifying the use of new target therapies already being tested in clinical trials.
    Keywords:  Cancer-specific survival; HIF-1α; Metabolic reprograming; Monocarboxylate Transporters; Overall survival; Prognosis; Renal cell cancer
    DOI:  https://doi.org/10.1093/carcin/bgab100
  34. Foods. 2021 Oct 14. pii: 2439. [Epub ahead of print]10(10):
    Metabolomics Based on 1H-NMR Reveal the Regulatory Mechanisms of Dietary Methionine Restriction on Splenic Metabolic Dysfunction in Obese Mice.
    Yuhui Yang, Jing Qian, Bowen Li, Manman Lu, Guowei Le, Yanli Xie.
      Methionine restriction (MR) has been reported to have many beneficial health effects, including stress resistance enhancement and lifespan extension. However, the effects of MR on the splenic metabolic dysfunction induced by obesity in mice remain unknown. This study aimed to investigate the scientific problem and clarify its possible mechanisms. C57BL/6J mice in the control group were fed a control diet (0.86% methionine, 4.2% fat) for 34 weeks, and others were fed a high-fat diet (0.86% methionine, 24% fat) for 10 weeks to establish diet-induced obese (DIO) mouse models. Then, the obtained DIO mice were randomly divided into two groups: the DIO group (DIO diet), the DIO + MR group (0.17% methionine, 24% fat) for 24 weeks. Our results indicated that MR decreased spleen weight, and spleen and plasma lipid profiles, promoted lipid catabolism and fatty acid oxidation, glycolysis and tricarboxylic acid cycle metabolism, and improved mitochondrial function and ATP generation in the spleen. Moreover, MR normalized the splenic redox state and inflammation-related metabolite levels, and increased plasma levels of immunoglobulins. Furthermore, MR increased percent lean mass and splenic crude protein levels, activated the autophagy pathway and elevated nucleotide synthesis to maintain protein synthesis in the spleen. These findings indicate that MR can ameliorate metabolic dysfunction by reducing lipid accumulation, oxidative stress, and inflammation in the spleen, and the mechanism may be the activation of autophagy pathway.
    Keywords:  autophagy; metabolism; metabolomics; methionine restriction; obesity; spleen injury
    DOI:  https://doi.org/10.3390/foods10102439
  35. Antioxidants (Basel). 2021 Oct 01. pii: 1569. [Epub ahead of print]10(10):
    Iron-Regulated Reactive Oxygen Species Production and Programmed Cell Death in Chronic Obstructive Pulmonary Disease.
    Kenji Mizumura, Yasuhiro Gon.
      Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation. However, the pathogenesis of COPD remains unclear. Currently, it is known to involve the loss of alveolar surface area (emphysema) and airway inflammation (bronchitis), primarily due to exposure to cigarette smoke (CS). CS causes epithelial cell death, resulting in pulmonary emphysema. Moreover, CS induces iron accumulation in the mitochondria and cytosol, resulting in programmed cell death. Although apoptosis has long been investigated as the sole form of programmed cell death in COPD, accumulating evidence indicates that a regulated form of necrosis, called necroptosis, and a unique iron-dependent form of non-apoptotic cell death, called ferroptosis, is implicated in the pathogenesis of COPD. Iron metabolism plays a key role in producing reactive oxygen species (ROS), including mitochondrial ROS and lipid peroxidation end-products, and activating both necroptosis and ferroptosis. This review outlines recent studies exploring CS-mediated iron metabolism and ROS production, along with the regulation of programmed cell death in COPD. Elucidating the mechanisms of these pathways may provide novel therapeutic targets for COPD.
    Keywords:  chronic obstructive pulmonary disease; ferroptosis; iron; mitochondrial damage; necroptosis; programmed cell death; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox10101569
  36. Int J Mol Sci. 2021 Oct 11. pii: 10946. [Epub ahead of print]22(20):
    Redox Homeostasis and Regulation in Pluripotent Stem Cells: Uniqueness or Versatility?
    Julia S Ivanova, Olga G Lyublinskaya.
      Pluripotent stem cells (PSCs) hold great potential both in studies on developmental biology and clinical practice. Mitochondrial metabolism that encompasses pathways that generate ATP and produce ROS significantly differs between PSCs and somatic cells. Correspondingly, for quite a long time it was believed that the redox homeostasis in PSCs is also highly specific due to the hypoxic niche of their origin-within the pre-implantation blastocyst. However, recent research showed that redox parameters of cultivated PSCs have much in common with that of their differentiated progeny cells. Moreover, it has been proven that, similar to somatic cells, maintaining the physiological ROS level is critical for the regulation of PSC identity, proliferation, differentiation, and de-differentiation. In this review, we aimed to summarize the studies of redox metabolism and signaling in PSCs to compare the redox profiles of pluripotent and differentiated somatic cells. We collected evidence that PSCs possess metabolic plasticity and are able to adapt to both hypoxia and normoxia, that pluripotency is not strictly associated with anaerobic conditions, and that cellular redox homeostasis is similar in PSCs and many other somatic cells under in vitro conditions that may be explained by the high conservatism of the redox regulation system.
    Keywords:  ROS; differentiation; pluripotent stem cells; proliferation; redox homeostasis; redox metabolism; redox signaling; somatic reprogramming
    DOI:  https://doi.org/10.3390/ijms222010946
  37. Biomed Res Int. 2021 ;2021 9949272
    Development of a KRAS-Associated Metabolic Risk Model for Prognostic Prediction in Pancreatic Cancer.
    Zuyi Ma, Zhenchong Li, Zuguang Ma, Zixuan Zhou, Hongkai Zhuang, Chunsheng Liu, Bowen Huang, Yiping Zou, Zehao Zheng, LinLing Yang, Yuanfeng Gong, Shanzhou Huang, Qi Zhou, Chuanzhao Zhang, Baohua Hou.
       Background: KRAS was reported to affect some metabolic genes and promote metabolic reprogramming in solid tumors. However, there was no comprehensive analysis to explore KRAS-associated metabolic signature or risk model for pancreatic cancer (PC).
    Methods: In the current study, multiple bioinformatics analyses were used to identify differentially expressed metabolic genes based on KRAS mutation status in PC. Then, we developed and validated a prognostic risk model based on the selected KRAS-associated metabolic genes. Besides, we explored the association between the risk model and the metabolic characteristics as well as gemcitabine-associated chemoresistance in PC.
    Results: 6 KRAS-associated metabolic genes (i.e., CYP2S1, GPX3, FTCD, ENPP2, UGT1A10, and XDH) were selected and enrolled to establish a prognostic risk model. The prognostic model had a high C-index of 0.733 for overall survival (OS) in TCGA pancreatic cancer database. The area under the curve (AUC) values of 1- and 3-year survival were both greater than 0.70. Then, the risk model was validated in two GEO datasets and also presented a satisfactory discrimination and calibration performance. Further, we found that the expression of some KRAS-driven glycolysis-associated genes (PKM, GLUT1, HK2, and LDHA) and gemcitabine-associated chemoresistance genes (i.e., CDA and RMM2) was significantly upregulated in high-risk PC patients evaluated by the risk model.
    Conclusions: We constructed a risk model based on 6 KRAS-associated metabolic genes, which predicted patients' survival with high accuracy and reflected tumor metabolic characteristics and gemcitabine-associated chemoresistance in PC.
    DOI:  https://doi.org/10.1155/2021/9949272
  38. Materials (Basel). 2021 Oct 11. pii: 5965. [Epub ahead of print]14(20):
    Potentiality of Nanoenzymes for Cancer Treatment and Other Diseases: Current Status and Future Challenges.
    Rakesh K Sindhu, Agnieszka Najda, Prabhjot Kaur, Muddaser Shah, Harmanpreet Singh, Parneet Kaur, Simona Cavalu, Monika Jaroszuk-Sierocińska, Md Habibur Rahman.
      Studies from past years have observed various enzymes that are artificial, which are issued to mimic naturally occurring enzymes based on their function and structure. The nanozymes possess nanomaterials that resemble natural enzymes and are considered an innovative class. This innovative class has achieved a brilliant response from various developments and researchers owing to this unique property. In this regard, numerous nanomaterials are inspected as natural enzyme mimics for multiple types of applications, such as imaging, water treatment, therapeutics, and sensing. Nanozymes have nanomaterial properties occurring with an inheritance that provides a single substitute and multiple platforms. Nanozymes can be controlled remotely via stimuli including heat, light, magnetic field, and ultrasound. Collectively, these all can be used to increase the therapeutic as well as diagnostic efficacies. These nanozymes have major biomedical applications including cancer therapy and diagnosis, medical diagnostics, and bio sensing. We summarized and emphasized the latest progress of nanozymes, including their biomedical mechanisms and applications involving synergistic and remote control nanozymes. Finally, we cover the challenges and limitations of further improving therapeutic applications and provide a future direction for using engineered nanozymes with enhanced biomedical and diagnostic applications.
    Keywords:  artificial; biomedical; cancer diagnosis; nanomaterials; nanozymes; therapeutics
    DOI:  https://doi.org/10.3390/ma14205965
  39. Pharmaceuticals (Basel). 2021 Sep 25. pii: 972. [Epub ahead of print]14(10):
    5-Aminolevulinic Acid Triggered by Ultrasound Halts Tumor Proliferation in a Syngeneic Model of Breast Cancer.
    Federica Foglietta, Giulia Gola, Elena Biasibetti, Maria Teresa Capucchio, Iside Bruni, Andrea Francovich, Gianni Durando, Loredana Serpe, Roberto Canaparo.
      Sonodynamic therapy is a bimodal therapeutic approach in which a chemical compound and ultrasound (US) synergistically act to elicit oxidative damage, triggering cancer cell death. Despite encouraging results, mainly for anticancer treatment, sonodynamics is still far from having a clinical application. Therefore, to close the gap between the bench and bedside, more in vivo studies are needed. In this investigation, the combined effect of 5-aminolevulinic acid (Ala), a natural porphyrin precursor, plus exposure to US, was investigated in vivo on a syngeneic breast cancer model. Real-time RT-PCR, Western blotting, and immunohistochemistry assays were performed to evaluate the effect of sonodynamic treatment on the main cancer hallmarks. The sonodynamic-treated group had a significant reduction (p ≤ 0.0001) in tumor size compared to the untreated group, and the Ala- and US-only treated groups, where a strong decrease (p ≤ 0.0001) in Ki67 protein expression was the most relevant feature of sonodynamic-treated cancer tissues. Moreover, oxidative stress was confirmed as the pivotal driver of the anticancer effect through cell cycle arrest, apoptosis, and autophagy; thus, sonodynamics should be explored further for cancer treatment.
    Keywords:  5-aminolevulinic acid; breast cancer; sonodynamic therapy; ultrasound
    DOI:  https://doi.org/10.3390/ph14100972
  40. Oncogene. 2021 Oct 19.
    Calcineurin inactivation inhibits pyruvate dehydrogenase complex activity and induces the Warburg effect.
    Jianong Zhang, Liang Zhang, Ji Nie, Yan Lin, Yao Li, Wei Xu, Jian-Yuan Zhao, Shi-Min Zhao, Chenji Wang.
      Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that connects the Ca2+-dependent signalling to multiple cellular responses. Calcineurin inhibitors (CNIs) have been widely used to suppress immune response in allograft patients. However, CNIs significantly increase cancer incidence in transplant recipients compared with the general population. Accumulating evidence suggests that CNIs may promote the malignant transformation of cancer cells in addition to its role in immunosuppression, but the underlying mechanisms remain poorly understood. Here, we show that calcineurin interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme that connects two key metabolic pathways of cells, glycolysis and the tricarboxylic acid cycle. Mitochondrial-localized calcineurin dephosphorylates PDHA1 at Ser232, Ser293 and Ser300, and thus enhances PDC enzymatic activity, remodels cellular glycolysis and oxidative phosphorylation, and suppresses cancer cell proliferation. Hypoxia attenuates mitochondrial translocation of calcineurin to promote PDC inactivation. Moreover, CNIs promote metabolic remodelling and the Warburg effect by blocking calcineurin-mediated PDC activation in cancer cells. Our findings indicate that calcineurin is a critical regulator of mitochondrial metabolism and suggest that CNIs may promote tumorigenesis through inhibition of the calcineurin-PDC pathway.
    DOI:  https://doi.org/10.1038/s41388-021-02065-0
  41. Oncogene. 2021 Oct 20.
    Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis.
    Shuyu Yu, Weicheng Zang, Yuchong Qiu, Liming Liao, Xiaofeng Zheng.
      Aberrant regulation of ubiquitination often leads to metabolic reprogramming in tumor cells. However, the underlying mechanisms are not fully understood. Here we demonstrate that OTUB2, an OTU deubiquitinase, is upregulated in colorectal cancer (CRC) and exacerbates the progression of CRC through modulating the aerobic glycolysis. Mechanistically, OTUB2 directly interacts with pyruvate kinase M2 (PKM2) and inhibits its ubiquitination by blocking the interaction between PKM2 and its ubiquitin E3 ligase Parkin, thereby enhancing PKM2 activity and promoting glycolysis. In response to glucose starvation stress, the effect of OTUB2 on PKM2 is enhanced, which confers metabolic advantage to CRC cells. Moreover, OTUB2 depletion reduces glucose consumption, lactate production, and cellular ATP production. OTUB2-knockout CRC cells exhibit attenuated proliferation and migration, as well as an elevated level of apoptosis and increased sensitivity to chemotherapy drugs. Furthermore, in vivo assays show that knockout of OTUB2 inhibits tumor growth in mice. Taken together, these findings reveal the critical role of OTUB2 in the regulation of glycolysis and illustrate the molecular mechanism underlying its role as a negative regulator of PKM2 ubiquitination in CRC, establishing a bridge between OTUB2-regulated PKM2 ubiquitination and altered metabolic patterns in CRC and suggesting that OTUB2 is a promising target for CRC treatment.
    DOI:  https://doi.org/10.1038/s41388-021-02071-2
  42. Biomolecules. 2021 Sep 28. pii: 1418. [Epub ahead of print]11(10):
    Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution.
    Richard B Parsons, Paul D Facey.
      Nicotinamide N-methyltransferase (NNMT) has progressed from being considered merely a Phase II metabolic enzyme to one with a central role in cell function and energy metabolism. Over the last three decades, a significant body of evidence has accumulated which clearly demonstrates a central role for NNMT in cancer survival, metastasis, and drug resistance. In this review, we discuss the evidence supporting a role for NNMT in the progression of the cancer phenotype and how it achieves this by driving the activity of pro-oncogenic NAD+-consuming enzymes. We also describe how increased NNMT activity supports the Warburg effect and how it promotes oncogenic changes in gene expression. We discuss the regulation of NNMT activity in cancer cells by both post-translational modification of the enzyme and transcription factor binding to the NNMT gene, and describe for the first time three long non-coding RNAs which may play a role in the regulation of NNMT transcription. We complete the review by discussing the development of novel anti-cancer therapeutics which target NNMT and provide insight into how NNMT-based therapies may be best employed clinically.
    Keywords:  NAD+; Warburg effect; cancer stem cell; drug resistance; methylation; oncogenesis; transcription factors; tumorigenesis
    DOI:  https://doi.org/10.3390/biom11101418
  43. Front Physiol. 2021 ;12 735532
    Lactate as an Astroglial Signal Augmenting Aerobic Glycolysis and Lipid Metabolism.
    Anemari Horvat, Robert Zorec, Nina Vardjan.
      Astrocytes, heterogeneous neuroglial cells, contribute to metabolic homeostasis in the brain by providing energy substrates to neurons. In contrast to predominantly oxidative neurons, astrocytes are considered primarily as glycolytic cells. They take up glucose from the circulation and in the process of aerobic glycolysis (despite the normal oxygen levels) produce L-lactate, which is then released into the extracellular space via lactate transporters and possibly channels. Astroglial L-lactate can enter neurons, where it is used as a metabolic substrate, or exit the brain via the circulation. Recently, L-lactate has also been considered to be a signaling molecule in the brain, but the mechanisms of L-lactate signaling and how it contributes to the brain function remain to be fully elucidated. Here, we provide an overview of L-lactate signaling mechanisms in the brain and present novel insights into the mechanisms of L-lactate signaling via G-protein coupled receptors (GPCRs) with the focus on astrocytes. We discuss how increased extracellular L-lactate upregulates cAMP production in astrocytes, most likely viaL-lactate-sensitive Gs-protein coupled GPCRs. This activates aerobic glycolysis, enhancing L-lactate production and accumulation of lipid droplets, suggesting that L-lactate augments its own production in astrocytes (i.e., metabolic excitability) to provide more L-lactate for neurons and that astrocytes in conditions of increased extracellular L-lactate switch to lipid metabolism.
    Keywords:  L-lactate; L-lactate sensitive receptors; aerobic glycolysis; astrocytes; cAMP; lipid metabolism
    DOI:  https://doi.org/10.3389/fphys.2021.735532
  44. Antioxidants (Basel). 2021 Oct 13. pii: 1606. [Epub ahead of print]10(10):
    Phytochemicals from Indian Ethnomedicines: Promising Prospects for the Management of Oxidative Stress and Cancer.
    Nishat Fatima, Syed Shabihe Raza Baqri, Ahmad Alsulimani, Sharmila Fagoonee, Petr Slama, Kavindra Kumar Kesari, Shubhadeep Roychoudhury, Shafiul Haque.
      Oxygen is indispensable for most organisms on the earth because of its role in respiration. However, it is also associated with several unwanted effects which may sometimes prove fatal in the long run. Such effects are more evident in cells exposed to strong oxidants containing reactive oxygen species (ROS). The adverse outcomes of oxidative metabolism are referred to as oxidative stress, which is a staple theme in contemporary medical research. Oxidative stress leads to plasma membrane disruption through lipid peroxidation and has several other deleterious effects. A large body of literature suggests the involvement of ROS in cancer, ageing, and several other health hazards of the modern world. Plant-based cures for these conditions are desperately sought after as supposedly safer alternatives to mainstream medicines. Phytochemicals, which constitute a diverse group of plant-based substances with varying roles in oxidative reactions of the body, are implicated in the treatment of cancer, aging, and all other ROS-induced anomalies. This review presents a summary of important phytochemicals extracted from medicinal plants which are a part of Indian ethnomedicine and Ayurveda and describes their possible therapeutic significance.
    Keywords:  ROS; cancer; ethnomedicine; oxidative stress; phytochemicals
    DOI:  https://doi.org/10.3390/antiox10101606
  45. J Cancer. 2021 ;12(21): 6372-6382
    CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity.
    Xiaopeng Cao, Ziman Zhu, Yi Cao, Jia Hu, Min Min.
      Background: The Warburg effect is closely associated with malignant phenotypes and poor prognosis in gastric cancer. CD73 is a glycosylphosphatidylinositol (GPI) anchored cell surface protein that functions as an oncogene in a variety of human cancers. However, the relationship between CD73 and the Warburg effect has yet to be fully understood. Methods: Integrative analysis was performed to identify glycolysis-related genes in gastric cancer. Loss-of-function and gain-of-function are performed to demonstrate the roles of CD73 in gastric cancer cell proliferation and glycolysis. Cell biological, molecular, and biochemical approaches are used to uncover the underlying mechanism. Results: In this study, we find that CD73 is a glycolysis-associated gene and is induced by hypoxia in gastric cancer. Genetic silencing of CD73 reduces gastric cancer cell proliferation and glycolytic ability. Opposite effects were observed by CD73 overexpression. Importantly, pharmacological inhibition of CD73 activity by APCP inhibits tumor growth, which can be largely compromised by the addition of adenosine, suggesting an enzyme activity-dependent effect of CD73 in gastric cancer. Furthermore, hijacking tumor glycolysis by 2-DG or galactose largely abrogated the oncogenic roles of CD73, indicating that CD73 promotes tumor growth in a glycolysis-dependent manner in gastric cancer. By the subcutaneous xenograft model, we confirmed the promotive roles of CD73 in regulating cell proliferation and glycolysis in gastric cancer. Conclusions: This study provides strong evidence of the involvement of CD73 in the Warburg effect and indicates that it could be a novel antitumor strategy to target tumor metabolism in gastric cancer.
    Keywords:  CD73; Gastric cancer; Hypoxia; NT5E; Warburg effect
    DOI:  https://doi.org/10.7150/jca.62387
  46. Mol Cancer Ther. 2021 Oct 19. pii: molcanther.0331.2021. [Epub ahead of print]
    DIRAS3: An Imprinted tumor suppressor gene that regulates RAS and PI3K-driven cancer growth, motility, autophagy and tumor dormancy.
    Gamze Bildik, Xiaowen Liang, Margie N Sutton, Robert C Bast, Zhen Lu.
      DIRAS3 is an imprinted tumor suppressor gene that encodes a 26 kD GTPase with 60% amino acid homology to RAS, but with a distinctive 34 amino acid N-terminal extension required to block RAS function. DIRAS3 is maternally imprinted and expressed only from the paternal allele in normal cells. Loss of expression can occur in a single "hit" through multiple mechanisms. Downregulation of DIRAS3 occurs in cancers of the ovary, breast, lung, prostate, colon, brain, and thyroid. Re-expression of DIRAS3 inhibits signaling through PI3 kinase/AKT, JAK/STAT and RAS/MAPK, blocking malignant transformation, inhibiting cancer cell growth and motility and preventing angiogenesis. DIRAS3 is a unique endogenous RAS inhibitor that binds directly to RAS, disrupting RAS dimers and clusters and preventing RAS-induced transformation. DIRAS3 is essential for autophagy and triggers this process through multiple mechanisms. Re-expression of DIRAS3 induces dormancy in a nu/nu mouse xenograft model of ovarian cancer, inhibiting cancer cell growth and angiogenesis. DIRAS3-mediated induction of autophagy facilitates the survival of dormant cancer cells in a nutrient-poor environment. DIRAS3 expression in dormant, drug-resistant autophagic cancer cells can serve as a biomarker and as a target for novel therapy to eliminate the residual disease that remains after conventional therapy.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-21-0331
  47. Antioxidants (Basel). 2021 Sep 29. pii: 1553. [Epub ahead of print]10(10):
    Preclinical and Clinical Antioxidant Effects of Natural Compounds against Oxidative Stress-Induced Epigenetic Instability in Tumor Cells.
    Abdelhakim Bouyahya, Naoual El Menyiy, Loubna Oumeslakht, Aicha El Allam, Abdelaali Balahbib, Abdur Rauf, Naveed Muhammad, Elena Kuznetsova, Marina Derkho, Muthu Thiruvengadam, Mohammad Ali Shariati, Nasreddine El Omari.
      ROS (reactive oxygen species) are produced via the noncomplete reduction in molecular oxygen in the mitochondria of higher organisms. The produced ROS are placed in various cell compartments, such as the mitochondria, cytoplasm, and endoplasmic reticulum. In general, there is an equilibrium between the synthesis of ROS and their reduction by the natural antioxidant defense system, called the redox system. Therefore, when this balance is upset, the excess ROS production can affect different macromolecules, such as proteins, lipids, nucleic acids, and sugars, which can lead to an electronic imbalance than oxidation of these macromolecules. Recently, it has also been shown that ROS produced at the cellular level can affect different signaling pathways that participate in the stimulation of transcription factors linked to cell proliferation and, consequently, to the carcinogenesis process. Indeed, ROS can activate the pathway of tyrosine kinase, MAP kinase, IKK, NF-KB, phosphoinositol 3 phosphate, and hypoxia-inducible factor (HIF). The activation of these signaling pathways directly contributes to the accelerated proliferation process and, as a result, the appearance of cancer. In addition, the use of antioxidants, especially natural ones, is now a major issue in the approach to cancer prevention. Some natural molecules, especially phytochemicals isolated from medicinal plants, have now shown interesting preclinical and clinical results.
    Keywords:  bioactive compounds; cancer; epigenetic; oxidative stress
    DOI:  https://doi.org/10.3390/antiox10101553
  48. Bioengineered. 2021 Oct 20.
    Combinative treatment of Curdione and docetaxel triggers reactive oxygen species (ROS)-mediated intrinsic apoptosis of triple-negative breast cancer cells.
    Changcheng Wang, Jia Guo, Zeng'an Wu.
      Traditional Chinese medicine Curcuma zedoary has been used for treating various diseases and cancers. However, the therapeutic effect of Curdione, one of its major components in triple negative breast cancer (TNBC) is still obscure. This study is aimed to explore whether combination of Curdione and docetaxel (DTX) could strengthen the DTX-induced pro-apoptotic effects in TNBC cells and identify its involved signaling pathways. In this study, combination of Curdione and DTX intensified the inhibited MDA-MB-468 cell proliferation and increased cell apoptosis caused by DTX treatment alone. Moreover, the combinative treatment of Curdione and DTX synergistically potentiated DTX-induced cell apoptosis by triggering reactive oxygen species (ROS) generation. Co-treatment with NAC (ROS inhibitor) could mostly block the effects induced by combination of Curdione and DTX. SB203580 (p38 inhibitor) or SC-79 (Akt activator) could partly reverse the effects induced by co-treatment, indicating that mitogen-actived protein kinases (MAPKs) and the phosphatidylinositol 3-kinases (PI3K) /Akt signaling pathway were involved in the co-treatment induced ROS-mediated cell apoptosis. To sum up, combination of Curdione and DTX enhanced the chemotherapeutic efficacy on MDA-MB-468 cells by triggering ROS-mediated cell apoptosis via MAPKs and PI3K/Akt signaling pathways. Curdione combined with DTX might have potentials application as the therapeutic strategy for TNBC.
    Keywords:  Curdione; chemo-sensitization; docetaxel; reactive oxygen species (ROS); triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.1080/21655979.2021.1994737
  49. Anticancer Agents Med Chem. 2021 Oct 21.
    Repurposing drugs as novel triple negative breast cancer therapeutics.
    Amiya Das, Pallavi Agarwal, Gaurav Kumar Jain, Geeta Aggarwal, Viney Lather, Deepti Pandita.
       BACKGROUND: Among all the types of breast cancer (BC), triple negative breast cancer (TNBC) is the most aggressive form having high metastasis and recurrence rate with limited treatment options. Conventional treatments such as chemotherapy and radiotherapy have lots of toxic side effects and also no FDA approved therapies are available till now. Repurposing of old clinically approved drugs towards various targets of TNBC is the new approach with lesser side effects and also leads to successful inexpensive drug development with less time consuming. Medicinal plants containg various phytoconstituents (flavonoids, alkaloids, phenols, essential oils, tanins, glycosides, lactones) plays very crucial role in combating various types of diseases and used in drug development process because of having lesser side effects.
    OBJECTIVE: The present review focuses in summarization of various categories of repurposed drugs against multitarget of TNBC and also summarizes the phytochemical categories that targets TNBC singly or in combination with synthetic old drugs.
    METHODS: Literature information was collected from various databases such as Pubmed, Web of Science, Scopus and Medline to understand and clarify the role and mechanism of repurposed synthetic drugs and phytoconstituents aginst TNBC by using keywords like "breast cancer", "repurposed drugs", "TNBC" and "phytoconstituents".
    RESULTS: Various repurposed drugs and phytochemicals targeting different signaling pathways that exerts their cytotoxic activities on TNBC cells ultimately leads to apoptosis of cells and also lowers the recurrence rate and stops the metastasis process.
    CONCLUSION: Inhibitory effects seen in different levels, which provides information and evidences to researchers towards drug developments process and thus further more investigations and researches need to be taken to get the better therapeutic treatment options against TNBC.
    Keywords:  Drug Repurposing; HSP90; PARP; Phytoconstituents; TNBC; apoptosis; signaling pathways
    DOI:  https://doi.org/10.2174/1871520621666211021143255
  50. Nutrients. 2021 Sep 30. pii: 3476. [Epub ahead of print]13(10):
    Time-Restricted Eating: A Novel and Simple Dietary Intervention for Primary and Secondary Prevention of Breast Cancer and Cardiovascular Disease.
    Rebecca A G Christensen, Amy A Kirkham.
      There is substantial overlap in risk factors for the pathogenesis and progression of breast cancer (BC) and cardiovascular disease (CVD), including obesity, metabolic disturbances, and chronic inflammation. These unifying features remain prevalent after a BC diagnosis and are exacerbated by BC treatment, resulting in elevated CVD risk among survivors. Thus, therapies that target these risk factors or mechanisms are likely to be effective for the prevention or progression of both conditions. In this narrative review, we propose time-restricted eating (TRE) as a simple lifestyle therapy to address many upstream causative factors associated with both BC and CVD. TRE is simple dietary strategy that typically involves the consumption of ad libitum energy intake within 8 h, followed by a 16-h fast. We describe the feasibility and safety of TRE and the available evidence for the impact of TRE on metabolic, cardiovascular, and cancer-specific health benefits. We also highlight potential solutions for overcoming barriers to adoption and adherence and areas requiring future research. In composite, we make the case for the use of TRE as a novel, safe, and feasible intervention for primary and secondary BC prevention, as well as tertiary prevention as it relates to CVD in BC survivors.
    Keywords:  breast cancer; cardiovascular disease; fasting; intermittent fasting; metabolic syndrome; time-restricted eating; time-restricted feeding
    DOI:  https://doi.org/10.3390/nu13103476
  51. Am J Cancer Res. 2021 ;11(9): 4199-4219
    Capsaicin exerts therapeutic effects by targeting tNOX-SIRT1 axis and augmenting ROS-dependent autophagy in melanoma cancer cells.
    Atikul Islam, Pei-Fang Hsieh, Pei-Fen Liu, Jou-Chun Chou, Jiunn-Wang Liao, Ming-Kun Hsieh, Pin Ju Chueh.
      Although considered a sporadic type of skin cancer, malignant melanoma has regularly increased internationally and is a major cause of cancer-associated death worldwide. The treatment options for malignant melanoma are very limited. Accumulating data suggest that the natural compound, capsaicin, exhibits preferential anticancer properties to act as a nutraceutical agent. Here, we explored the underlying molecular events involved in the inhibitory effect of capsaicin on melanoma growth. The cellular thermal shift assay (CETSA), isothermal dose-response fingerprint curves (ITDRFCETSA), and CETSA-pulse proteolysis were utilized to confirm the direct binding of capsaicin with the tumor-associated NADH oxidase, tNOX (ENOX2) in melanoma cells. We also assessed the cellular impact of capsaicin-targeting of tNOX on A375 cells by flow cytometry and protein analysis. The essential role of tNOX in tumor- and melanoma-growth limiting abilities of capsaicin was evaluated in C57BL/6 mice. Our data show that capsaicin directly engaged with cellular tNOX to inhibit its enzymatic activity and enhance protein degradation capacity. The inhibition of tNOX by capsaicin was accompanied by the attenuation of SIRT1, a NAD+-dependent deacetylase. The suppression of tNOX and SIRT1 then enhanced ULK1 acetylation and induced ROS-dependent autophagy in melanoma cells. Capsaicin treatment of mice implanted with melanoma cancer cells suppressed tumor growth by down-regulating tNOX and SIRT1, which was also seen in an in vivo xenograft study with tNOX-depleted melanoma cells. Taken together, our findings suggest that tNOX expression is important for the growth of melanoma cancer cells both in vitro and in vivo, and that inhibition of the tNOX-SIRT1 axis contributes to inducting ROS-dependent autophagy in melanoma cells.
    Keywords:  Autophagy; CETSA-pulse proteolysis; cellular thermal shift assay (CETSA); melanoma; reactive oxygen species (ROS); sirtuin 1 (silent mating type information regulation 2 homolog 1 or SIRT1); tumor-associated NADH oxidase (tNOX or ENOX2)
  52. Pharmaceuticals (Basel). 2021 Oct 02. pii: 1015. [Epub ahead of print]14(10):
    Pharmacometabolomics by NMR in Oncology: A Systematic Review.
    Nuria Gómez-Cebrián, Pedro Vázquez Ferreiro, Francisco Javier Carrera Hueso, José Luis Poveda Andrés, Leonor Puchades-Carrasco, Antonio Pineda-Lucena.
      Pharmacometabolomics (PMx) studies aim to predict individual differences in treatment response and in the development of adverse effects associated with specific drug treatments. Overall, these studies inform us about how individuals will respond to a drug treatment based on their metabolic profiles obtained before, during, or after the therapeutic intervention. In the era of precision medicine, metabolic profiles hold great potential to guide patient selection and stratification in clinical trials, with a focus on improving drug efficacy and safety. Metabolomics is closely related to the phenotype as alterations in metabolism reflect changes in the preceding cascade of genomics, transcriptomics, and proteomics changes, thus providing a significant advance over other omics approaches. Nuclear Magnetic Resonance (NMR) is one of the most widely used analytical platforms in metabolomics studies. In fact, since the introduction of PMx studies in 2006, the number of NMR-based PMx studies has been continuously growing and has provided novel insights into the specific metabolic changes associated with different mechanisms of action and/or toxic effects. This review presents an up-to-date summary of NMR-based PMx studies performed over the last 10 years. Our main objective is to discuss the experimental approaches used for the characterization of the metabolic changes associated with specific therapeutic interventions, the most relevant results obtained so far, and some of the remaining challenges in this area.
    Keywords:  drug response; metabolism; nuclear magnetic resonance; personalized medicine; pharmacometabolomics
    DOI:  https://doi.org/10.3390/ph14101015
  53. Oncogene. 2021 Oct 18.
    Loss of the wild-type KRAS allele promotes pancreatic cancer progression through functional activation of YAP1.
    Han Yan, Chih-Chieh Yu, Stuart A Fine, Ayman Lee Youssof, Ye-Ran Yang, Jun Yan, Dillon C Karg, Edwin C Cheung, Richard A Friedman, Haoqiang Ying, Emily I Chen, Ji Luo, Yi Miao, Wanglong Qiu, Gloria H Su.
      Human pancreatic ductal adenocarcinoma (PDAC) harboring one KRAS mutant allele often displays increasing genomic loss of the remaining wild-type (WT) allele (known as LOH at KRAS) as tumors progress to metastasis, yet the molecular ramification of this WT allelic loss is unknown. In this study, we showed that the restoration of WT KRAS expression in human PDAC cell lines with LOH at KRAS significantly attenuated the malignancy of PDAC cells both in vitro and in vivo, demonstrating a tumor-suppressive role of the WT KRAS allele. Through RNA-Seq, we identified the HIPPO signaling pathway to be positively regulated by WT KRAS in PDAC cells. In accordance with this observation, PDAC cells with LOH at KRAS exhibited increased nuclear localization and activation of transcriptional co-activator YAP1. Mechanistically, we discovered that WT KRAS expression sequestered YAP1 from the nucleus, through enhanced 14-3-3zeta interaction with phosphorylated YAP1 at S127. Consistently, expression of a constitutively-active YAP1 mutant in PDAC cells bypassed the growth inhibitory effects of WT KRAS. In patient samples, we found that the YAP1-activation genes were significantly upregulated in tumors with LOH at KRAS, and YAP1 nuclear localization predicted poor survival for PDAC patients. Collectively, our results reveal that the WT allelic loss leads to functional activation of YAP1 and enhanced tumor malignancy, which explains the selection advantage of the tumor cells with LOH at KRAS during pancreatic cancer clonal evolution and progression to metastasis, and should be taken into consideration in future therapeutic strategies targeting KRAS.
    DOI:  https://doi.org/10.1038/s41388-021-02040-9
  54. Nat Metab. 2021 Oct;3(10): 1290-1301
    The metabolic roots of senescence: mechanisms and opportunities for intervention.
    Christopher D Wiley, Judith Campisi.
      Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.
    DOI:  https://doi.org/10.1038/s42255-021-00483-8
  55. Metabolites. 2021 Sep 29. pii: 668. [Epub ahead of print]11(10):
    Metabolic Tumor Microenvironment Characterization of Contrast Enhancing Brain Tumors Using Physiologic MRI.
    Andreas Stadlbauer, Franz Marhold, Stefan Oberndorfer, Gertraud Heinz, Max Zimmermann, Michael Buchfelder, Elisabeth Heynold, Thomas M Kinfe.
      The tumor microenvironment is a critical regulator of cancer development and progression as well as treatment response and resistance in brain neoplasms. The available techniques for investigation, however, are not well suited for noninvasive in vivo characterization in humans. A total of 120 patients (59 females; 61 males) with newly diagnosed contrast-enhancing brain tumors (64 glioblastoma, 20 brain metastases, 15 primary central nervous system (CNS) lymphomas (PCNSLs), and 21 meningiomas) were examined with a previously established physiological MRI protocol including quantitative blood-oxygen-level-dependent imaging and vascular architecture mapping. Six MRI biomarker maps for oxygen metabolism and neovascularization were fused for classification of five different tumor microenvironments: glycolysis, oxidative phosphorylation (OxPhos), hypoxia with/without neovascularization, and necrosis. Glioblastoma showed the highest metabolic heterogeneity followed by brain metastasis with a glycolysis-to-OxPhos ratio of approximately 2:1 in both tumor entities. In addition, glioblastoma revealed a significant higher percentage of hypoxia (24%) compared to all three other brain tumor entities: brain metastasis (7%; p < 0.001), PCNSL (8%; p = 0.001), and meningioma (8%; p = 0.003). A more aggressive biological brain tumor behavior was associated with a higher percentage of hypoxia and necrosis and a lower percentage of remaining vital tumor tissue and aerobic glycolysis. The proportion of oxidative phosphorylation, however, was rather similar (17-26%) for all four brain tumor entities. Tumor microenvironment (TME) mapping provides insights into neurobiological differences of contrast-enhancing brain tumors and deserves further clinical cancer research attention. Although there is a long roadmap ahead, TME mapping may become useful in order to develop new diagnostic and therapeutic approaches.
    Keywords:  brain tumors; energy metabolism; hypoxia; metabolic imaging; neovascularization; physiological MRI; tumor microenvironment
    DOI:  https://doi.org/10.3390/metabo11100668
  56. Front Oncol. 2021 ;11 704353
    The Interplay Between Prostate Cancer Genomics, Metabolism, and the Epigenome: Perspectives and Future Prospects.
    Reema Singh, Ian G Mills.
      Prostate cancer is a high-incidence cancer, often detected late in life. The prostate gland is an accessory gland that secretes citrate; an impaired citrate secretion reflects imbalances in the activity of enzymes in the TCA Cycle in mitochondria. Profiling studies on prostate tumours have identified significant metabolite, proteomic, and transcriptional modulations with an increased mitochondrial metabolic activity associated with localised prostate cancer. Here, we focus on the androgen receptor, c-Myc, phosphatase and tensin Homolog deleted on chromosome 10 (PTEN), and p53 as amongst the best-characterised genomic drivers of prostate cancer implicated in metabolic dysregulation and prostate cancer progression. We outline their impact on metabolic function before discussing how this may affect metabolite pools and in turn chromatin structure and the epigenome. We reflect on some recent literature indicating that mitochondrial mutations and OGlcNAcylation may also contribute to this crosstalk. Finally, we discuss the technological challenges of assessing crosstalk given the significant differences in the spatial sensitivity and throughput of genomic and metabolomic profiling approaches.
    Keywords:  TCA cycle; epigenetics; metabolism; mitochondria; prostate cancer
    DOI:  https://doi.org/10.3389/fonc.2021.704353
  57. Front Mol Biosci. 2021 ;8 735303
    A Key Silencing Histone Mark on Chromatin Is Lost When Colorectal Adenocarcinoma Cells Are Depleted of Methionine by Methionine γ-Lyase.
    Samanta Raboni, Serena Montalbano, Stephanie Stransky, Benjamin A Garcia, Annamaria Buschini, Stefano Bettati, Simone Sidoli, Andrea Mozzarelli.
      Methionine is an essential amino acid used, beyond protein synthesis, for polyamine formation and DNA/RNA/protein methylation. Cancer cells require particularly high methionine supply for their homeostasis. A successful approach for decreasing methionine concentration is based on the systemic delivery of methionine γ-lyase (MGL), with in vitro and in vivo studies demonstrating its efficacy in cancer therapy. However, the mechanisms explaining how cancer cells suffer from the absence of methionine more significantly than non-malignant cells are still unclear. We analyzed the outcome of the human colorectal adenocarcinoma cancer cell line HT29 to the exposure of MGL for up to 72 h by monitoring cell viability, proteome expression, histone post-translational modifications, and presence of spurious transcription. The rationale of this study was to verify whether reduced methionine supply would affect chromatin decondensation by changing the levels of histone methylation and therefore increasing genomic instability. MGL treatment showed a time-dependent cytotoxic effect on HT29 cancer cells, with an IC50 of 30 µg/ml, while Hs27 normal cells were less affected, with an IC50 of >460 µg/ml. Although the levels of total histone methylation were not altered, a loss of the silencing histone mark H3K9me2 was observed, as well as a decrease in H4K20me3. Since H3K9me2/3 decorate repetitive DNA elements, we proved by qRT-PCR that MGL treatment leads to an increased expression of major satellite units. Our data indicate that selected histone methylation marks may play major roles in the mechanism of methionine starvation in cancer cells, proving that MGL treatment directly impacts chromatin homeostasis.
    Keywords:  cancer therapy; enzyme-based therapy; histone methylation; mass spectrometry; methionine
    DOI:  https://doi.org/10.3389/fmolb.2021.735303
  58. ACS Med Chem Lett. 2021 Oct 14. 12(10): 1512-1513
    Dual Inhibition of KRAS G12C and G12D Mutants as a Potential Treatment in Cancer Therapy.
    Robert B Kargbo.
      
    DOI:  https://doi.org/10.1021/acsmedchemlett.1c00441
  59. Biochem Cell Biol. 2021 Oct 22.
    PDGFRβ Modulates Aerobic Glycolysis in Osteosarcoma HOS Cells via the PI3K/AKT/mTOR/c-Myc Pathway.
    Hu-Ying Tang, Jia-Qi Guo, Bo-Tao Sang, Jun-Ning Cheng, Xiang-Mei Wu.
      Osteosarcoma is a malignant tumor abundant in vascular tissue, and its rich blood supply may have a significant impact on its metabolic characteristics. PDGFRβ is a membrane receptor highly expressed in osteosarcoma cells and vascular wall cells, and its effect on osteosarcoma metabolism needs to be further studied. In this study, we discussed the effect and mechanism of PDGFRβ on the glucose metabolism of osteosarcomaHOS cells. First, GSEA, Pearson's correlation test, and PPI correlation analysis indicated the positive regulation of PDGFRβ on aerobic glycolysis in osteosarcoma. The results of qPCR and western blot further confirmed the prediction of bioinformatics. Glucose metabolism experiments proved that PDGF/PDGFRβ couldeffectively promote the aerobic glycolysis of osteosarcoma cells. In addition, the mitochondrial membrane potential experiment proved that the metabolic change triggered by PDGFRβ was not caused by mitochondrial damage. PI3K pathway inhibitor LY294002 or MEK pathway inhibitor U0126, or Warburg effect inhibitor DCA was used to carry out western blot and glucose metabolism experiments, and the results showed that PDGFBB/PDGFRβ mainly activated the PI3K/AKT/mTOR/ c-Myc pathway to promote aerobic glycolysis in osteosarcoma HOS cells. The newly elucidated role of PDGFRβ provides a novel metabolic therapeutic target for osteosarcoma.
    DOI:  https://doi.org/10.1139/bcb-2021-0305
  60. Toxics. 2021 Oct 11. pii: 259. [Epub ahead of print]9(10):
    Influence of Dietary Compounds on Arsenic Metabolism and Toxicity. Part II-Human Studies.
    Monika Sijko, Lucyna Kozłowska.
      Exposure to various forms of arsenic (As), the source of which may be environmental as well as occupational exposure, is associated with many adverse health effects. Therefore, methods to reduce the adverse effects of As on the human body are being sought. Research in this area focuses, among other topics, on the dietary compounds that are involved in the metabolism of this element. Therefore, the aim of this review was to analyze the influence of methionine, betaine, choline, folic acid, vitamin B2, B6, B12 and zinc on the efficiency of inorganic As (iAs) metabolism and the reduction in the severity of the whole spectrum of disorders related to As exposure. In this review, which included 62 original papers (human studies) we present the current knowledge in the area. In human studies, these compounds (methionine, choline, folic acid, vitamin B2, B6, B12 and zinc) may increase iAs metabolism and reduce toxicity, whereas their deficiency may impair iAs metabolism and increase As toxicity. Taking into account the results of studies conducted in populations exposed to As, it is reasonable to carry out prophylactic activities. In particular nutritional education seems to be important and should be focused on informing people that an adequate intake of those dietary compounds potentially has a modulating effect on iAs metabolism, thus, reducing its adverse effects on the body.
    Keywords:  detoxification; exposure; inorganic arsenic; metal toxicity; methylation; minerals; vitamins
    DOI:  https://doi.org/10.3390/toxics9100259
  61. Cell Chem Biol. 2021 Oct 20. pii: S2451-9456(21)00434-7. [Epub ahead of print]
    Screening compound libraries for H2O2-mediated cancer therapeutics using a peroxiredoxin-based sensor.
    Yining Hao, Troy F Langford, Sun Jin Moon, Kristen A Eller, Hadley D Sikes.
      Compounds that modulate H2O2 reaction networks have applications as targeted cancer therapeutics, as a subset of cancers exhibit sensitivity to this redox signal. Previous studies to identify therapeutics that induce oxidants have relied upon probes that respond to many different oxidants in cells, and thus do not report on only H2O2, a redox signal that selectively oxidizes proteins. Here we use a genetically encoded fluorescent probe for human peroxiredoxin-2 (Prx2) oxidation in screens for small-molecule compounds that modulate H2O2 pathways. We further characterize cellular responses to several compounds selected from the screen. Our results reveal that some, but not all, of the compounds enact H2O2-mediated toxicity in cells. Among them, SMER3, an antifungal, has not been reported as an oxidant-inducing drug. Several drugs, including cisplatin, that previously have been shown to induce reactive oxygen species (ROS) do not appear to oxidize Prx2, suggesting H2O2 is not among the ROS induced by those drugs.
    Keywords:  biosensor; cancer; genetically encoded H(2)O(2) specific sensor; high-throughput drug screening; oxidative stress; peroxiredoxin; reactive oxygen species; redox metabolism; redox therapeutics
    DOI:  https://doi.org/10.1016/j.chembiol.2021.09.003
  62. Macromol Biosci. 2021 Oct 17. e2100304
    Advances in Hyaluronic acid-based (nano)devices for Cancer Therapy.
    Francesca Della Sala, Antonio Fabozzi, Mario di Gennaro, Stefano Nuzzo, Pooyan Makvandi, Nicola Solimando, Maurizio Pagliuca, Assunta Borzacchiello.
      Cancer is the main cause of fatality all over the world with a considerable growth rate. Many biologically active nanoplatforms have been exploited for tumor treatment. Of nanodevices, hyaluronic acid (HA)-based systems have shown to be promising candidates for cancer therapy due to their high biocompatibility and cell internalization. Herein, surface functionalization of different nanoparticles, e.g. organic- and inorganic-based nanoparticles are highlighted. Subsequently, HA-based nanostructures and their applications in cancer therapy are presented. This article is protected by copyright. All rights reserved.
    Keywords:  Cancer therapy; cell internalization; functionalization; hyaluronic acid; surface modifications
    DOI:  https://doi.org/10.1002/mabi.202100304
  63. Cancers (Basel). 2021 Oct 15. pii: 5176. [Epub ahead of print]13(20):
    Could Photodynamic Therapy Be a Promising Therapeutic Modality in Hepatocellular Carcinoma Patients? A Critical Review of Experimental and Clinical Studies.
    Abhishek Kumar, Olivier Moralès, Serge Mordon, Nadira Delhem, Emmanuel Boleslawski.
      Photodynamic Therapy (PDT) relies on local or systemic administration of a light-sensitive dye, called photosensitizer, to accumulate into the target site followed by excitation with light of appropriate wavelength and fluence. This photo-activated molecule reacts with the intracellular oxygen to induce selective cytotoxicity of targeted cells by the generation of reactive oxygen species. Hepatocellular carcinoma (HCC), one of the leading causes of cancer-associated mortality worldwide, has insufficient treatment options available. In this review, we discuss the mechanism and merits of PDT along with its recent developments as an anti-cancerous therapy. We also highlight the application of this novel therapy for diagnosis, visualization, and treatment of HCC. We examine the underlying challenges, some pre-clinical and clinical studies, and possibilities of future studies associated with PDT. Finally, we discuss the mechanism of an active immune response by PDT and thereafter explored the role of PDT in the generation of anti-tumor immune response in the context of HCC, with an emphasis on checkpoint inhibitor-based immunotherapy. The objective of this review is to propose PDT as a plausible adjuvant to existing therapies for HCC, highlighting a feasible combinatorial approach for HCC treatment.
    Keywords:  active targeting; anti-cancer therapy; anti-tumor immunity; cirrhosis; passive targeting
    DOI:  https://doi.org/10.3390/cancers13205176
  64. Front Bioeng Biotechnol. 2021 ;9 761218
    Nanosonosensitizers With Ultrasound-Induced Reactive Oxygen Species Generation for Cancer Sonodynamic Immunotherapy.
    Danling Cheng, Xiaoying Wang, Xiaojun Zhou, Jingchao Li.
      Immunotherapy is a promising therapeutic strategy for cancer, while it has been demonstrated to encounter the issues of low immune responses and underlying immune-related adverse events. The sonodynamic therapy (SDT) that utilizes sonosensitizers to produce reactive oxygen species (ROS) triggered by ultrasound (US) stimulation can be used to ablate tumors, which also leads to the induction of immunogenic cell death (ICD), thus achieving SDT-induced immunotherapy. Further combination of SDT with immunotherapy is able to afford enhanced antitumor immunity for tumor regression. In this mini review, we summarize the recent development of nanosonosensitizers with US-induced ROS generation for cancer SDT immunotherapy. The uses of nanosonosensitizers to achieve SDT-induced immunotherapy, combinational therapy of SDT with immunotherapy, and combinational therapy of SDT with multiple immunotherapies are briefly introduced. Furthermore, the current concerns and perspectives for the development and further clinical applications of these nanosonosensitizers for SDT-combined immunotherapy of cancer are discussed.
    Keywords:  immunotherapy; nanosonosensitizers; reactive oxygen species; sonodynamic therapy; ultrasound
    DOI:  https://doi.org/10.3389/fbioe.2021.761218
  65. Per Med. 2021 Oct 18.
    After decades, RAS mutation has finally become a therapeutic target.
    Nabih Naim, Sara Moukheiber, Karim Jaber, Hampig Raphael Kourie.
      
    Keywords:  AMG 510; KRAS; KRAS G12C; NSCLC; RAS; adagrasib; cancer; proto-oncogene; sotorasib; targeted therapies
    DOI:  https://doi.org/10.2217/pme-2021-0015
  66. Int J Mol Sci. 2021 Oct 18. pii: 11221. [Epub ahead of print]22(20):
    Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment.
    Nagaja Capitani, Laura Patrussi, Cosima T Baldari.
      Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish metastases. In the tumor microenvironment, cytotoxic T cells-the specialized tumor-cell killers-also show this dual nature, operating their tumor-cell directed killing activities until they become exhausted and dysfunctional, a process promoted by cancer cells themselves. Here, we discuss the opposing activities of immune cells populating the tumor microenvironment in both cancer progression and anti-cancer responses, with a focus on cytotoxic T cells and on the molecular mechanisms responsible for the efficient suppression of their killing activities as a paradigm of the power of cancer cells to shape the microenvironment for their own survival and expansion.
    Keywords:  cytotoxic T cells; exhaustion; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms222011221
  67. Eur J Intern Med. 2021 Oct 17. pii: S0953-6205(21)00329-0. [Epub ahead of print]
    The impact of nutrition and lifestyle modification on health.
    Lèlita Santos.
      The main recommendations from public health entities include healthy diets and physical activity as the main lifestyle factors impacting the development of chronic diseases such as cardiovascular and metabolic diseases, cancer, and even neurological diseases. Randomized clinical trials have been designed to demonstrate those lifestyle modifications can change the pattern of chronic diseases development and progression. Among these, nutrition is one of the most impacting factors. Therefore, nutrition and diets were also included in different randomized clinical trials, and most of them showed a favorable impact of nutrition modification on the participant's health. Nevertheless, study designs were considerably different, and future studies are needed to support nutrition modifications further. The choice of a healthy considered diet, like the Mediterranean diet, was shown to impact chronic diseases, cardiovascular risk, and adult life expectancy mainly due to its anti-inflammatory and antioxidant properties. Furthermore, a high intake of fibers, fruits, and vegetables together with a low intake of fat and energy-dense, processed foods contribute to an inflammation reduction and a more robust immune system leading. Besides these well-known properties, all lifestyle modifications must be personalized according to the availability of foods, geographic localizations, and the healthy status of the patient.
    Keywords:  Diet; Dietary patterns; Lifestyle medicine; Mediterranean diet; Nutrition
    DOI:  https://doi.org/10.1016/j.ejim.2021.09.020
  68. Cells. 2021 Oct 02. pii: 2641. [Epub ahead of print]10(10):
    Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression.
    Chun-Chao Wang.
      Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances focus on how tumors develop pro-proliferative metabolic signaling that differs them from adjacent, non-transformed epithelial tissues. This leads to targetable oncogene-driven liabilities among breast cancer subtypes. Other advances demonstrate how microenvironments trigger stress-response at single-cell resolution. Microenvironmental heterogeneities give rise to cell regulatory states in cancer cell spheroids in three-dimensional cultures and at stratified terminal end buds during mammary gland morphogenesis, where stress and survival signaling juxtapose. The cell-state specificity in stress signaling networks recapture metabolic evolution during cancer progression. Understanding lineage-specific metabolic phenotypes in experimental models is useful for gaining a deeper understanding of subtype-selective breast cancer metabolism.
    Keywords:  3D spheroid culture; breast cancer progression; mammary gland morphogenesis; metabolic stress; terminal end bud
    DOI:  https://doi.org/10.3390/cells10102641
  69. Cancers (Basel). 2021 Oct 13. pii: 5124. [Epub ahead of print]13(20):
    Targeting the Redox Balance Pathway Using Ascorbic Acid in sdhb Zebrafish Mutant Larvae.
    Margo Dona, Maaike Lamers, Svenja Rohde, Marnix Gorissen, Henri J L M Timmers.
      Patients with mutations in the β-subunit of the succinate dehydrogenase (SDHB) have the highest risk to develop incurable malignant phaeochromocytomas and paragangliomas (PPGLs). Therapy development is hindered by limited possibilities to test new therapeutic strategies in vivo. One possible molecular mechanism of SDHB-associated tumorigenesis originates in an overproduction of reactive oxygen species (ROS) due to mitochondrial dysfunction. Ascorbic acid (Vitamin C) has already been shown to act as anti-cancer agent in several clinical trials for various types of cancer. In this study, the potential of the sdhbrmc200 zebrafish model to study SDHB-associated PPGLs using a drug screening approach was investigated. First, we identified increased basal ROS levels in homozygous sdhb larvae compared to heterozygous and wild-type siblings. Using a semi high-throughput drug screening, the effectiveness of different dosages of anti- and pro-oxidant Vitamin C were assessed to evaluate differences in survival, ROS levels, and locomotor activity. Low-dosage levels of Vitamin C induced a decrease of ROS levels but no significant effects on lifespan. In contrast, high-dosage levels of Vitamin C shortened the lifespan of the homozygous sdhbrmc200 larvae while not affecting the lifespan of heterozygous and wild-type siblings. These results validated the sdhbrmc200 zebrafish model as a powerful drug screening tool that may be used to identify novel therapeutic targets for SDHB-associated PPGLs.
    Keywords:  Vitamin C; cancer; drug discovery; mitochondrial complex II; paraganglioma; phaeochromocytoma; redox balance pathway; therapy; zebrafish
    DOI:  https://doi.org/10.3390/cancers13205124
  70. Biomolecules. 2021 Oct 08. pii: 1485. [Epub ahead of print]11(10):
    Protocatechuic Acid, a Simple Plant Secondary Metabolite, Induced Apoptosis by Promoting Oxidative Stress through HO-1 Downregulation and p21 Upregulation in Colon Cancer Cells.
    Rosaria Acquaviva, Barbara Tomasello, Claudia Di Giacomo, Rosa Santangelo, Alfonsina La Mantia, Irina Naletova, Maria Grazia Sarpietro, Francesco Castelli, Giuseppe Antonio Malfa.
      Gastrointestinal cancers, particularly colorectal cancer, are mainly influenced by the dietary factor. A diet rich in fruits and vegetables can help to reduce the incidence of colorectal cancer thanks to the phenolic compounds, which possess antimutagenic and anticarcinogenic properties. Polyphenols, alongside their well-known antioxidant properties, also show a pro-oxidative potential, which makes it possible to sensitize tumor cells to oxidative stress. HO-1 combined with antioxidant activity, when overexpressed in cancer cells, is involved in tumor progression, and its inhibition is considered a feasible therapeutic strategy in cancer treatment. In this study, the effects of protocatechuic acid (PCA) on the viability of colon cancer cells (CaCo-2), annexin V, LDH release, reactive oxygen species levels, total thiol content, HO-1, γ-glutamylcysteine synthetase, and p21 expression were evaluated. PCA induced, in a dose-dependent manner, a significantly reduced cell viability of CaCo-2 by oxidative/antioxidant imbalance. The phenolic acid induced modifications in levels of HO-1, non-proteic thiol groups, γ-glutamylcysteine synthetase, reactive oxygen species, and p21. PCA induced a pro-oxidant effect in cancer cells, and the in vitro pro-apoptotic effect on CaCo-2 cells is mediated by the modulation of redox balance and the inhibition of the HO-1 system that led to the activation of p21. Our results suggest that PCA may represent a useful tool in prevention and/or therapy of colon cancer.
    Keywords:  CaCo-2; LDH leakage; annexin V; p21; phenolic acids; prooxidants; total thiol groups; γ-GCS
    DOI:  https://doi.org/10.3390/biom11101485
  71. Cells. 2021 Oct 09. pii: 2707. [Epub ahead of print]10(10):
    Redox Control of the Dormant Cancer Cell Life Cycle.
    Bowen Li, Yichun Huang, Hui Ming, Edouard C Nice, Rongrong Xuan, Canhua Huang.
      Following efficient tumor therapy, some cancer cells may survive through a dormancy process, contributing to tumor recurrence and worse outcomes. Dormancy is considered a process where most cancer cells in a tumor cell population are quiescent with no, or only slow, proliferation. Recent advances indicate that redox mechanisms control the dormant cancer cell life cycle, including dormancy entrance, long-term dormancy, and metastatic relapse. This regulatory network is orchestrated mainly through redox modification on key regulators or global change of reactive oxygen species (ROS) levels in dormant cancer cells. Encouragingly, several strategies targeting redox signaling, including sleeping, awaking, or killing dormant cancer cells are currently under early clinical evaluation. However, the molecular mechanisms underlying redox control of the dormant cancer cell cycle are poorly understood and need further exploration. In this review, we discuss the underlying molecular basis of redox signaling in the cell life cycle of dormant cancer and the potential redox-based targeting strategies for eliminating dormant cancer cells.
    Keywords:  ROS; cancer dormancy; cancer therapy; redox signaling
    DOI:  https://doi.org/10.3390/cells10102707
  72. Biochem Pharmacol. 2021 Oct 18. pii: S0006-2952(21)00429-9. [Epub ahead of print] 114813
    Chrysin induces autophagy-dependent ferroptosis to increase chemosensitivity to gemcitabine by targeting CBR1 in pancreatic cancer cells.
    Ling Zhou, Chen Yang, Weilan Zhong, Qiaoyun Wang, Daolai Zhang, Jiayu Zhang, Shuyang Xie, Maolei Xu.
      Recent studies have verified that inducing reactive oxygen species (ROS) is one of the gemcitabine anti-tumor mechanisms of action. Human carbonyl reductase 1 (CBR1) plays an important role in protecting cells against oxidative damage. However, it is unclear whether CBR1 is involved in pancreatic cancer (PC) progression and resistance to gemcitabine. Based on the GEPIA database, we analyzed tumor tissue samples from PC patients using immunohistochemistry (IHC) and revealed that CBR1 was highly expressed in PC tissues and that this was significantly correlated with the clinicopathological features of PC. Genetic inhibition of CBR1 suppressed PC cell proliferation by regulating ROS generation. Furthermore, gemcitabine upregulated CBR1 expression, which could limit the anti-tumor activity of gemcitabine, and attenuation of CBR1 enhanced gemcitabine sensitivity in vitro and in vivo. Additionally, we report that chrysin directly binds to CBR1, which inhibited its enzymatic activity both at the molecular and cellular levels. Inhibition of CBR1 by chrysin increased cellular ROS levels and led to ROS-dependent autophagy, which resulted in the degradation of ferritin heavy polypeptide 1 (FTH1) and an increase in the intracellular free iron level that participates in ferroptosis in PC cells. Finally, our results showed that chrysin enhanced PC sensitivity to gemcitabine by inducing ferroptotic death in vitro and in vivo. Collectively, these findings indicate that CBR1 is a potential therapeutic target for PC treatment. In addition, we elucidated a novel mechanism underlying the anti-tumor effects of chrysin.
    Keywords:  autophagy; carbonyl reductase 1; chrysin; ferroptosis; gemcitabine resistance; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.bcp.2021.114813
  73. Nanomaterials (Basel). 2021 Oct 18. pii: 2757. [Epub ahead of print]11(10):
    Biomedical Applications of Chinese Herb-Synthesized Silver Nanoparticles by Phytonanotechnology.
    Rehmat Islam, Leming Sun, Lianbing Zhang.
      Recent advances in nanotechnology have opened up new avenues for the controlled synthesis of nanoparticles for biomedical and pharmaceutical applications. Chinese herbal medicine is a natural gift to humanity, and it has long been used as an antibacterial and anticancer agent. This study will highlight recent developments in the phytonanotechnological synthesis of Chinese herbal medicines to utilize their bioactive components in biomedical and therapeutic applications. Biologically synthesized silver nanoparticles (AgNPs) have emerged as a promising alternative to chemical and physical approaches for various biomedical applications. The comprehensive rationale of combinational or synergistic effects of Chinese herb-based AgNPs synthesis was investigated with superior physicochemical and biological properties, and their biomedical applications, including antimicrobial and anticancer activity and wound healing properties. AgNPs can damage the cell ultrastructure by triggering apoptosis, which includes the formation of reactive oxygen species (ROS), DNA disintegration, protein inactivation, and the regulation of various signaling pathways. However, the anticancer mechanism of Chinese herbal medicine-based AgNPs is more complicated due to the potential toxicity of AgNPs. Further in-depth studies are required to address Chinese herbs' various bioactive components and AgNPs as a synergistic approach to combat antimicrobial resistance, therapeutic efficiency of drug delivery, and control and prevention of newly emerged diseases.
    Keywords:  Chinese herbal; bioactive molecules; biomedical applications; phytonanotechnology; silver nanoparticles
    DOI:  https://doi.org/10.3390/nano11102757
  74. ACS Med Chem Lett. 2021 Oct 14. 12(10): 1514-1516
    Modulation of KRAS Mutant by Inhibiting PLK1 Kinase in Cancer Therapeutics.
    Robert B Kargbo.
      
    DOI:  https://doi.org/10.1021/acsmedchemlett.1c00442
  75. Antioxidants (Basel). 2021 Oct 11. pii: 1591. [Epub ahead of print]10(10):
    Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells.
    Saniya Ossikbayeva, Marina Khanin, Yoav Sharoni, Aviram Trachtenberg, Sultan Tuleukhanov, Richard Sensenig, Slava Rom, Michael Danilenko, Zulfiya Orynbayeva.
      Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in vivo and can also be (geno)toxic to at least some types of normal cells. The ability of certain polyphenols to synergize with one another at low concentrations can be used as a promising strategy to effectively treat human malignancies. We have recently reported that curcumin and carnosic acid applied at non-cytotoxic concentrations synergistically cooperate to induce massive apoptosis in acute myeloid leukemia cells, but not in normal hematopoietic and non-hematopoietic cells, via sustained cytosolic calcium overload. Here, we show that the two polyphenols can also synergistically suppress the growth of DU145 and PC-3 metastatic prostate cancer cell cultures. However, instead of cell killing, the combined treatment induced a marked inhibition of cell proliferation associated with G0/G1 cell cycle arrest. This was preceded by transient elevation of cytosolic calcium levels and prolonged dissipation of the mitochondrial membrane potential, without generating oxidative stress, and was associated with defective oxidative phosphorylation encompassing mitochondrial dysfunction. The above effects were concomitant with a significant downregulation of mRNA and protein expression of the oncogenic kinase SGK1, the mitochondria-hosted mTOR component. In addition, a moderate decrease in SGK1 phosphorylation at Ser422 was observed in polyphenol-treated cells. The mTOR inhibitor rapamycin produced a similar reduction in SGK1 mRNA and protein levels as well as phosphorylation. Collectively, our findings suggest that the combination of curcumin and carnosic acid at potentially bioavailable concentrations may effectively target different types of cancer cells by distinct modes of action. This and similar combinations merit further exploration as an anticancer modality.
    Keywords:  OxPhos; SGK1; carnosic acid; cell cycle; curcumin; prostate cancer
    DOI:  https://doi.org/10.3390/antiox10101591
  76. Cells. 2021 Oct 15. pii: 2768. [Epub ahead of print]10(10):
    Functional Proteomic Profiling of Triple-Negative Breast Cancer.
    Irina Gromova, Jaime A Espinoza, Morten Grauslund, Eric Santoni-Rugiu, Maj-Lis Møller Talman, Jan van Oostrum, José M A Moreira.
      Triple-negative breast cancer (TNBC) is a subtype of breast cancer that comprises various disease entities, all of which share a set of common features: a lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, respectively. Because of their receptor status, conventional chemotherapy remains the main therapeutic option for TNBC patients. We employed a reverse phase protein array approach (RPPA), complemented by immunohistochemistry, to quantitatively profile the activation state of 84 actionable key signaling intermediates and phosphoproteins in a set of 44 TNBC samples. We performed supervised and unsupervised approaches to proteomic data analysis to identify groups of samples sharing common characteristics that could be amenable to existing therapies. We found the heterogenous activation of multiple pathways, with PI3 K/AKT/mTOR signaling being the most common event. Some specific individualized therapeutic possibilities include the expression of oncogenic KIT in association with cytokeratin 15 and Erk1/2 positive tumors, both of which may have clinical value.
    Keywords:  breast cancer; proteomics; reverse phase protein array; signaling pathway profiling; triple negative breast cancer
    DOI:  https://doi.org/10.3390/cells10102768
  77. Pharmaceutics. 2021 Sep 22. pii: 1538. [Epub ahead of print]13(10):
    Developing Actively Targeted Nanoparticles to Fight Cancer: Focus on Italian Research.
    Monica Argenziano, Silvia Arpicco, Paola Brusa, Roberta Cavalli, Daniela Chirio, Franco Dosio, Marina Gallarate, Elena Peira, Barbara Stella, Elena Ugazio.
      Active targeting is a valuable and promising approach with which to enhance the therapeutic efficacy of nanodelivery systems, and the development of tumor-targeted nanoparticles has therefore attracted much research attention. In this field, the research carried out in Italian Pharmaceutical Technology academic groups has been focused on the development of actively targeted nanosystems using a multidisciplinary approach. To highlight these efforts, this review reports a thorough description of the last 10 years of Italian research results on the development of actively targeted nanoparticles to direct drugs towards different receptors that are overexpressed on cancer cells or in the tumor microenvironment. In particular, the review discusses polymeric nanocarriers, liposomes, lipoplexes, niosomes, solid lipid nanoparticles, squalene nanoassemblies and nanobubbles. For each nanocarrier, the main ligands, conjugation strategies and target receptors are described. The literature indicates that polymeric nanoparticles and liposomes stand out as key tools for improving specific drug delivery to the site of action. In addition, solid lipid nanoparticles, squalene nanoparticles and nanobubbles have also been successfully proposed. Taken together, these strategies all offer many platforms for the design of nanocarriers that are suitable for future clinical translation.
    Keywords:  active targeting; cancer therapy; ligand; liposomes; nanobubbles; polymeric nanocarriers; receptor; solid lipid nanoparticles
    DOI:  https://doi.org/10.3390/pharmaceutics13101538
  78. Biomolecules. 2021 Oct 19. pii: 1546. [Epub ahead of print]11(10):
    Hyperhomocysteinemia: Metabolic Role and Animal Studies with a Focus on Cognitive Performance and Decline-A Review.
    Hendrik Nieraad, Nina Pannwitz, Natasja de Bruin, Gerd Geisslinger, Uwe Till.
      Disturbances in the one-carbon metabolism are often indicated by altered levels of the endogenous amino acid homocysteine (HCys), which is additionally discussed to causally contribute to diverse pathologies. In the first part of the present review, we profoundly and critically discuss the metabolic role and pathomechanisms of HCys, as well as its potential impact on different human disorders. The use of adequate animal models can aid in unravelling the complex pathological processes underlying the role of hyperhomocysteinemia (HHCys). Therefore, in the second part, we systematically searched PubMed/Medline for animal studies regarding HHCys and focused on the potential impact on cognitive performance and decline. The majority of reviewed studies reported a significant effect of HHCys on the investigated behavioral outcomes. Despite of persistent controversial discussions about equivocal findings, especially in clinical studies, the present evaluation of preclinical evidence indicates a causal link between HHCys and cognition-related- especially dementia-like disorders, and points out the further urge for large-scale, well-designed clinical studies in order to elucidate the normalization of HCys levels as a potential preventative or therapeutic approach in human pathologies.
    Keywords:  animal; dementia; disease models; hyperhomocysteinemia; vitamin B deficiency
    DOI:  https://doi.org/10.3390/biom11101546
  79. J Oncol. 2021 ;2021 3006853
    The Multifaceted Therapeutic Mechanisms of Curcumin in Osteosarcoma: State-of-the-Art.
    Fatemeh Zahedipour, Monireh Bolourinezhad, Yong Teng, Amirhossein Sahebkar.
      Osteosarcoma is a major form of malignant bone tumor that typically occurs in young adults and children. The combination of aggressive surgical strategies and chemotherapy has led to improvements in survival time, although individuals with recurrent or metastatic conditions still have an extremely poor prognosis. This disappointing situation strongly indicates that testing novel, targeted therapeutic agents is imperative to prevent the progression of osteosarcoma and enhance patient survival time. Curcumin, a naturally occurring phenolic compound found in Curcuma longa, has been shown to have a wide variety of anti-tumor, anti-oxidant, and anti-inflammatory activities in many types of cancers including osteosarcoma. Curcumin is a highly pleiotropic molecule that can modulate intracellular signaling pathways to regulate cell proliferation, inflammation, and apoptosis. These signaling pathways include RANK/RANKL, Notch, Wnt/β-catenin, apoptosis, autophagy, JAK/STAT, and HIF-1 pathways. Additionally, curcumin can regulate the expression of various types of microRNAs that are involved in osteosarcoma. Therefore, curcumin may be a potential candidate for the prevention and treatment of osteosarcoma. This comprehensive review not only covers the use of curcumin in the treatment of osteosarcoma and its anti-cancer molecular mechanisms but also reveals the novel delivery strategies and combination therapies with the aim to improve the therapeutic effect of curcumin.
    DOI:  https://doi.org/10.1155/2021/3006853
  80. Front Oncol. 2021 ;11 736104
    Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab.
    Riccardo Giampieri, Alessio Lupi, Pina Ziranu, Alessandro Bittoni, Andrea Pretta, Federica Pecci, Mara Persano, Enrica Giglio, Cecilia Copparoni, Sonia Crocetti, Alessandra Mandolesi, Gavino Faa, Pierpaolo Coni, Mario Scartozzi, Rossana Berardi.
       Background: KRAS mutations in metastatic colorectal cancer (mCRC) define a subset of tumors that have primary resistance to anti-EGFR-based therapy. Data concerning whether different KRAS mutations may also have a prognostic value are lacking. Furthermore, novel KRAS G12C inhibitors are currently in development. The aim of our analysis was to compare response rates in patients treated with first-line chemotherapy doublet + Bevacizumab among different KRAS variants. Secondary end-points were progression free survival (PFS) and overall survival (OS).
    Methods: Patients with KRAS mutated mCRC treated with either FOLFIRI/FOLFOX/XELOX + Bevacizumab were eligible for enrollment. Patients whose tumor harbored NRAS mutations or that coexpressed also BRAF mutations were excluded from this retrospective analysis. Patients' individual data were collected from patients' records. Propensity score matching (nearest method, 1:2 ratio) was used to define the two different groups of patients for comparison (KRAS G12C mutated vs other KRAS variants). Eastern Cooperative Oncology Group Performance Status (ECOG PS), sex, metastatic site of involvement, synchronous vs metachronous metastatic disease, tumor sidedness, mucinous histology, primary tumor surgery, more than two lines of treatment for metastatic disease, and radical surgery of metastases were used as matching factors. Response rate (RR) was calculated by RECIST 1.1 criteria. Both progression free-survival and overall survival were calculated by Kaplan-Meier method. Categorical variables were compared by Fisher exact test for binomial variables and by chi-square test for all other instances. The level of statistical significance p was set at 0.05 for all tests.
    Results: A total of 120 patients were assessed in the final analysis. Out of the 120 patients, 15 (12%) were KRAS G12C mutated. In the whole cohort of patients, 59/120 (49%) had partial response (PR), 42/120 (35%) had stable disease (SD), and 19/120 (16%) had progressive disease (PD) as the best response. In KRAS G12C patients, 4/15 (27%) had PR, 6/15 (40%) had SD, and the remaining 5/15 (33%) had PD as the best response. In patients with other KRAS mutations, 55/105 (52%) had PR, 37/105 (35%) had SD, and the remaining 13/105 (12%) had PD as the best response. The difference in RR between the two groups of patients was statistically significant (p=0.017). On the other hand, no difference in PFS (p=0.76) and OS (p=0.56) was observed. After matching procedures, the difference in response rates between KRAS G12C mutated patients vs the matched cohort of patients with other KRAS mutations remained statistically significant (p=0.016). KRAS G12C mutations were not associated with differences in sites of metastatic involvement, sex, and ECOG PS. On the other hand, synchronous vs metachronous metastatic disease (p=0.039), age > 75 years (p=0.043), and mucinous histology (p=0.008) were more frequent in G12C mutated tumors.
    Conclusions: In our cohort of patients, it was observed that KRAS G12C mutations are associated with worse response rates compared to other KRAS variants when treated with standard chemotherapy doublet + Bevacizumab. On the other hand, both PFS and OS were not significantly different. Based on these findings, we believe that new treatment options focused on KRAS G12C inhibition should be tested mainly in first-line setting and in addition to standard chemotherapy doublet + Bevacizumab for mCRC patients, as they might "fill the gap" in response rates that was seen in our study.
    Keywords:  G12C; KRAS; chemotherapy; first line; mCRC
    DOI:  https://doi.org/10.3389/fonc.2021.736104
  81. Antioxidants (Basel). 2021 Oct 12. pii: 1600. [Epub ahead of print]10(10):
    Anthocyanins in Colorectal Cancer Prevention Review.
    Ni Shi, Xiaoxin Chen, Tong Chen.
      Colorectal cancer (CRC) is still a big health burden worldwide. Nutrition and dietary factors are known to affect colorectal cancer development and prognosis. The protective roles of diets rich in fruits and vegetables have been previously reported to contain high levels of cancer-fighting phytochemicals. Anthocyanins are the most abundant flavonoid compounds that are responsible for the bright colors of most blue, purple, and red fruits and vegetables, and have been shown to contribute to the protective effects of fruits and vegetables against cancer and other chronic diseases. Berries and grapes are the most common anthocyanin-rich fruits with antitumor effects. The antitumor effects of anthocyanins are determined by their structures and bioavailability as well as how they are metabolized. In this review, we aimed to discuss the preventive as well as therapeutic potentials of anthocyanins in CRC. We summarized the antitumor effects of anthocyanins and the mechanisms of action. We also discussed the potential pharmaceutical application of anthocyanins in practice.
    Keywords:  anthocyanins; antitumor effect; berries; colorectal cancer; grapes; phytochemicals
    DOI:  https://doi.org/10.3390/antiox10101600
  82. Nutrients. 2021 Sep 28. pii: 3421. [Epub ahead of print]13(10):
    Fasting and Exercise in Oncology: Potential Synergism of Combined Interventions.
    Rebekah L Wilson, Dong-Woo Kang, Cami N Christopher, Tracy E Crane, Christina M Dieli-Conwright.
      Nutrition and exercise interventions are strongly recommended for most cancer patients; however, much debate exists about the best prescription. Combining fasting with exercise is relatively untouched within the oncology setting. Separately, fasting has demonstrated reductions in chemotherapy-related side effects and improved treatment tolerability and effectiveness. Emerging evidence suggests fasting may have a protective effect on healthy cells allowing chemotherapy to exclusively target cancer cells. Exercise is commonly recommended and attenuates treatment- and cancer-related adverse changes to body composition, quality of life, and physical function. Given their independent benefits, in combination, fasting and exercise may induce synergistic effects and further improve cancer-related outcomes. In this narrative review, we provide a critical appraisal of the current evidence of fasting and exercise as independent interventions in the cancer population and discuss the potential benefits and mechanisms of combined fasting and exercise on cardiometabolic, body composition, patient-reported outcomes, and cancer-related outcomes. Our findings suggest that within the non-cancer population combined fasting and exercise is a viable strategy to improve health-related outcomes, however, its safety and efficacy in the oncology setting remain unknown. Therefore, we also provide a discussion on potential safety issues and considerations for future research in the growing cancer population.
    Keywords:  cancer; exercise; fasting; nutrition
    DOI:  https://doi.org/10.3390/nu13103421
  83. Am J Cancer Res. 2021 ;11(9): 4141-4174
    Bio-nanoparticle based therapeutic vaccine induces immunogenic response against triple negative breast cancer.
    Xuewei Bai, Yanmei Zhou, Qiushi Lin, Chiung-Kuei Huang, Songhua Zhang, Rolf I Carlson, Hossein Ghanbari, Bei Sun, Jack R Wands, Xiaoqun Dong.
      Triple negative breast cancer (TNBC) is more aggressive and has a poorer prognosis than other sub-types of breast tumors. This study elucidates how aspartate beta-hydroxylase (ASPH) network promotes drug resistance, and immunotherapy targeting ASPH may improve the efficacy of Doxorubicin (DOX) therapy. An orthotopic model of breast cancer generated by 4T1 cells in immunocompetent mice was used to explore efficacy of immunotherapy in combination with DOX chemotherapy. We evaluated mRNA and protein expression in cultured tumor cells and tissue, as well as assessed cell proliferation, apoptosis, soluble factors/cytokine production, immune cell population diversity and function. We observed that ASPH expression enables TNBC cells to exhibit primary resistance to DOX induced single-/double-strand breaks (SSB/DSB) and enhanced proliferation and survival. Specific bio-nanoparticle based therapeutic vaccine (BNP-TV) promoted ASPH uptake by and maturation of DCs. This BNP-TV combined with DOX induces immunogenic cell death (ICD) in orthotopic xenograft tumors and significantly suppressed primary mammary tumor growth and distant multi-organ metastases. Immunogenic cell death induced by BNP-TV targeting ASPH combined with DOX provides opportunities to treat a highly resistant and metastatic form of breast cancer.
    Keywords:  Aspartate β-hydroxylase; doxorubicin; immunogenic cell death; metastasis; λ-phage
  84. Front Endocrinol (Lausanne). 2021 ;12 732190
    Myoglobin Protects Breast Cancer Cells Due to Its ROS and NO Scavenging Properties.
    Theresa Quinting, Anna Katharina Heymann, Anne Bicker, Theresa Nauth, Andre Bernardini, Thomas Hankeln, Joachim Fandrey, Timm Schreiber.
      Myoglobin (MB) is an oxygen-binding protein usually found in cardiac myocytes and skeletal muscle fibers. It may function as a temporary storage and transport protein for O2 but could also have scavenging capacity for reactive oxygen and nitrogen species. In addition, MB has recently been identified as a hallmark in luminal breast cancer and was shown to be robustly induced under hypoxia. Cellular responses to hypoxia are regulated by the transcription factor hypoxia-inducible factor (HIF). For exploring the function of MB in breast cancer, we employed the human cell line MDA-MB-468. Cells were grown in monolayer or as 3D multicellular spheroids, which mimic the in vivo avascular tumor architecture and physiology with a heterogeneous cell population of proliferating cells in the rim and non-cycling or necrotic cells in the core region. This central necrosis was increased after MB knockdown, indicating a role for MB in hypoxic tumor regions. In addition, MB knockdown caused higher levels of HIF-1α protein after treatment with NO, which also plays an important role in cancer cell survival. MB knockdown also led to higher reactive oxygen species (ROS) levels in the cells after treatment with H2O2. To further explore the role of MB in cell survival, we performed RNA-Seq after MB knockdown and NO treatment. 1029 differentially expressed genes (DEGs), including 45 potential HIF-1 target genes, were annotated in regulatory pathways that modulate cellular function and maintenance, cell death and survival, and carbohydrate metabolism. Of these target genes, TMEFF1, TREX2, GLUT-1, MKNK-1, and RAB8B were significantly altered. Consistently, a decreased expression of GLUT-1, MKNK-1, and RAB8B after MB knockdown was confirmed by qPCR. All three genes of interest are often up regulated in cancer and correlate with a poor clinical outcome. Thus, our data indicate that myoglobin might influence the survival of breast cancer cells, possibly due to its ROS and NO scavenging properties and could be a valuable target for cancer therapy.
    Keywords:  HIF; NO; ROS; breast cancer; hypoxia; myoglobin; tumor
    DOI:  https://doi.org/10.3389/fendo.2021.732190
  85. Tissue Eng Regen Med. 2021 Oct 21.
    Tumor Microenvironment Modulating Functional Nanoparticles for Effective Cancer Treatments.
    Seungyong Shin, Jiyoung Lee, Jieun Han, Fangyuan Li, Daishun Ling, Wooram Park.
      Cancer is one of the major diseases that threaten human life worldwide. Despite advances in cancer treatment techniques, such as radiation therapy, chemotherapy, targeted therapy, and immunotherapy, it is still difficult to cure cancer because of the resistance mechanism of cancer cells. Current understanding of tumor biology has revealed that resistance to these anticancer therapies is due to the tumor microenvironment (TME) represented by hypoxia, acidity, dense extracellular matrix, and immunosuppression. This review demonstrates the latest strategies for effective cancer treatment using functional nanoparticles that can modulate the TME. Indeed, preclinical studies have shown that functional nanoparticles can effectively modulate the TME to treat refractory cancer. This strategy of using TMEs with controllable functional nanoparticles is expected to maximize cancer treatment efficiency in the future by combining it with various modern cancer therapeutics.
    Keywords:  Biomaterials; Cancer treatments; Drug delivery; Nanoparticles; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s13770-021-00403-7
  86. Pharmaceutics. 2021 Oct 17. pii: 1715. [Epub ahead of print]13(10):
    Improving Curcumin Bioavailability: Current Strategies and Future Perspectives.
    Rita Tabanelli, Simone Brogi, Vincenzo Calderone.
      Curcumin possesses a plethora of interesting pharmacological effects. Unfortunately, it is also characterized by problematic drug delivery and scarce bioavailability, representing the main problem related to the use of this compound. Poor absorption, fast metabolism, and rapid systemic clearance are the most important factors contributing to low curcumin levels in plasma and tissues. Accordingly, to overcome these issues, numerous strategies have been proposed and are investigated in this article. Due to advances in the drug delivery field, we describe here the most promising strategies for increasing curcumin bioavailability, including the use of adjuvant, complexed/encapsulated curcumin, specific curcumin formulations, and curcumin nanoparticles. We analyze current strategies, already available in the market, and the most advanced technologies that can offer a future perspective for effective curcumin formulations. We focus the attention on the effectiveness of curcumin-based formulations in clinical trials, providing a comprehensive summary. Clinical trial results, employing various delivery methods for curcumin, showed that improved bioavailability corresponds to increased therapeutic efficacy. Furthermore, advances in the field of nanoparticles hold great promise for developing curcumin-based complexes as effective therapeutic agents. Summarizing, suitable delivery methods for this polyphenol will ensure the possibility of using curcumin-derived formulations in clinical practice as preventive and disease-modifying therapeutics.
    Keywords:  bioavailability; curcumin; delivery by design; delivery methods; nanoparticles
    DOI:  https://doi.org/10.3390/pharmaceutics13101715
  87. RSC Med Chem. 2021 Sep 23. 12(9): 1604-1611
    Small molecule-mediated induction of endoplasmic reticulum stress in cancer cells.
    Shalini Pandey, Virender Kumar Sharma, Ankur Biswas, Mayurika Lahiri, Sudipta Basu.
      The endoplasmic reticulum (ER) is one of the crucial sub-cellular organelles controlling myriads of functions including protein biosynthesis, folding, misfolding and unfolding. As a result, dysregulation of these pathways in the ER is implicated in cancer development and progression. Subsequently, targeting the ER in cancer cells emerged as an interesting unorthodox strategy in next-generation anticancer therapy. However, development of small molecules to selectively target the ER for cancer therapy remained elusive and unexplored. To address this, herein, we have developed a novel small molecule library of sulfonylhydrazide-hydrazones through a short and concise chemical synthetic strategy. We identified a fluorescent small molecule that localized into the endoplasmic reticulum (ER) of HeLa cells, induced ER stress followed by triggering autophagy which was subsequently inhibited by chloroquine (autophagy inhibitor) to initiate apoptosis. This small molecule showed remarkable cancer cell killing efficacy in different cancer cells as mono and combination therapy with chloroquine, thus opening a new direction to illuminate ER-biology towards the development of novel anticancer therapeutics.
    DOI:  https://doi.org/10.1039/d1md00095k
  88. Antioxidants (Basel). 2021 Sep 30. pii: 1560. [Epub ahead of print]10(10):
    Selenium-Catalyzed Reduction of Hydroperoxides in Chemistry and Biology.
    Laura Orian, Leopold Flohé.
      Among the chalcogens, selenium is the key element for catalyzed H2O2 reduction. In organic synthesis, catalytic amounts of organo mono- and di-selenides are largely used in different classes of oxidations, in which H2O2 alone is poorly efficient. Biological hydroperoxide metabolism is dominated by peroxidases and thioredoxin reductases, which balance hydroperoxide challenge and contribute to redox regulation. When their selenocysteine is replaced by cysteine, the cellular antioxidant defense system is impaired. Finally, classes of organoselenides have been synthesized with the aim of mimicking the biological strategy of glutathione peroxidases, but their therapeutic application has so far been limited. Moreover, their therapeutic use may be doubted, because H2O2 is not only toxic but also serves as an important messenger. Therefore, over-optimization of H2O2 reduction may lead to unexpected disturbances of metabolic regulation. Common to all these systems is the nucleophilic attack of selenium to one oxygen of the peroxide bond promoting its disruption. In this contribution, we revisit selected examples from chemistry and biology, and, by using results from accurate quantum mechanical modelling, we provide an accurate unified picture of selenium's capacity of reducing hydroperoxides. There is clear evidence that the selenoenzymes remain superior in terms of catalytic efficiency.
    Keywords:  catalysis; deselenylation; diphenyl diselenide; ebselen; glutathione peroxidases; hydrogen peroxide; hydroxy perhydroxy selenane; selenenic acid; selenocysteine
    DOI:  https://doi.org/10.3390/antiox10101560
  89. Nanoscale. 2021 Oct 21.
    Host-cell-assisted construction of a folate-engineered nanocarrier based on viral light particles for targeted cancer therapy.
    Cheng Lv, Jian Ao, Ji Wang, Man Tang, An-An Liu, Dai-Wen Pang.
      Targeted cancer therapy has aroused the broad interest of researchers due to its accuracy in specific tumor targeting and its few side effects on normal cells. In the last decades, oncolytic viral light particles (L-particles) have been transformed into smart nanocarriers for targeted drug delivery. However, these L-particles, similar to the oncolytic viruses that they are derived from, can only recognize tumor cells expressing corresponding receptors, severely limiting their universal application. Although modification of targeting agents onto their envelope can overcome this limitation, it is still a great challenge to do so without interfering with their biofunction since the envelope is fragile. Herein, a host-cell-assisted strategy is proposed to construct folate-engineered nanocarriers (F-L-particles) with their biofunctions maintained to the largest extent. The F-L-particles were further multi-functionalized by encapsulating ultrasmall near-infrared quantum dots and antitumor drugs in them for tumor real-time imaging and therapy. Such a moderate, efficient and convenient cell-based strategy facilitates the development and widespread application of these bio-nanocarriers in the field of targeted cancer therapy, and drives the interdisciplinary studies of nanotechnology, chemistry, and virology.
    DOI:  https://doi.org/10.1039/d1nr04903h
  90. J Med Chem. 2021 Oct 18.
    Targeted Delivery and Site-Specific Activation of β-Cyclodextrin-Conjugated Photosensitizers for Photodynamic Therapy through a Supramolecular Bio-orthogonal Approach.
    Evelyn Y Xue, Wen-Jing Shi, Wing-Ping Fong, Dennis K P Ng.
      Targeted delivery of photosensitizers using hydrophilic and tumor-directing carriers and site-specific activation of their photocytotoxicity are two common strategies to enhance the specificity of anticancer photodynamic therapy. We report herein a novel supramolecular bio-orthogonal approach to integrate these two functions. A β-cyclodextrin-substituted aza-boron-dipyrromethene-based photosensitizer was first complexed with a ferrocene-substituted black-hole quencher to inhibit its photosensitizing ability. Upon encountering the adamantane moieties that had been delivered to target cancer cells through specific binding of the conjugated peptide to the overexpressed epidermal growth factor receptor, the ferrocene-based guest species were displaced due to the stronger binding interactions between β-cyclodextrin and adamantane, thereby restoring the photodynamic activity of the photosensitizer. Hence, this two-step process enabled targeted delivery and site-specific activation of the photosensitizer, as demonstrated through a series of experiments in aqueous media, in a range of cancer cell lines and in tumor-bearing nude mice.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c01505
  91. J Hematol Oncol. 2021 Oct 21. 14(1): 173
    Neutrophils in cancer carcinogenesis and metastasis.
    Shumin Xiong, Liaoliao Dong, Lin Cheng.
      In recent years, neutrophils have attracted increasing attention because of their cancer-promoting effects. An elevated neutrophil-to-lymphocyte ratio is considered a prognostic indicator for patients with cancer. Neutrophils are no longer regarded as innate immune cells with a single function, let alone bystanders in the pathological process of cancer. Their diversity and plasticity are being increasingly recognized. This review summarizes previous studies assessing the roles and mechanisms of neutrophils in cancer initiation, progression, metastasis and relapse. Although the findings are controversial, the fact that neutrophils play a dual role in promoting and suppressing cancer is undeniable. The plasticity of neutrophils allows them to adapt to different cancer microenvironments and exert different effects on cancer. Given the findings from our own research, we propose a reasonable hypothesis that neutrophils may be reprogrammed into a cancer-promoting state in the cancer microenvironment. This new perspective indicates that neutrophil reprogramming in the course of cancer treatment is a problem worthy of attention. Preventing or reversing the reprogramming of neutrophils may be a potential strategy for adjuvant cancer therapy.
    Keywords:  Cancer; Cell plasticity; Cell reprogramming; Microenvironment; Neutrophil
    DOI:  https://doi.org/10.1186/s13045-021-01187-y
  92. Biomedicines. 2021 Oct 14. pii: 1476. [Epub ahead of print]9(10):
    Antitumoral Activities of Curcumin and Recent Advances to ImProve Its Oral Bioavailability.
    Marta Claudia Nocito, Arianna De Luca, Francesca Prestia, Paola Avena, Davide La Padula, Lucia Zavaglia, Rosa Sirianni, Ivan Casaburi, Francesco Puoci, Adele Chimento, Vincenzo Pezzi.
      Curcumin, a main bioactive component of the Curcuma longa L. rhizome, is a phenolic compound that exerts a wide range of beneficial effects, acting as an antimicrobial, antioxidant, anti-inflammatory and anticancer agent. This review summarizes recent data on curcumin's ability to interfere with the multiple cell signaling pathways involved in cell cycle regulation, apoptosis and the migration of several cancer cell types. However, although curcumin displays anticancer potential, its clinical application is limited by its low absorption, rapid metabolism and poor bioavailability. To overcome these limitations, several curcumin-based derivatives/analogues and different drug delivery approaches have been developed. Here, we also report the anticancer mechanisms and pharmacokinetic characteristics of some derivatives/analogues and the delivery systems used. These strategies, although encouraging, require additional in vivo studies to support curcumin clinical applications.
    Keywords:  bioavailability; cancer cells; curcumin; curcumin analogues; curcumin delivery systems; curcumin derivatives
    DOI:  https://doi.org/10.3390/biomedicines9101476
  93. Comp Biochem Physiol A Mol Integr Physiol. 2021 Oct 19. pii: S1095-6433(21)00206-3. [Epub ahead of print] 111098
    Prolonged cortisol elevation alters whole body and tissue metabolism in rainbow trout (Oncorhynchus mykiss).
    Tilo Pfalzgraff, Ivar Lund, Peter Vilhelm Skov.
      Chronic elevation of circulating cortisol is known to have deleterious effects on fish, but information about the consequences of prolonged cortisol elevation on the metabolism of fish is scarce. To test the effects of chronic cortisol elevation on the aerobic performance of rainbow trout, we examined how two severities of chronically elevated plasma cortisol levels affected the oxygen uptake during rest and after exhaustive exercise using a high (HC) and a medium cortisol (MC) treatment. High cortisol doses significantly affected standard (SMR) and maximum metabolic rates (MMR) compared to control fish. In comparison, the medium cortisol treatment elevated maximum metabolic rates (MMR) but did not significantly influence SMR compared to a sham group (S) and control group (C). The medium cortisol treatment resulted in a significantly increased metabolic scope due to an elevation of MMR, an effect that was abolished in the HC group due to co-occuring elevations in SMR. The elevated SMR of the HC-treated fish could be explained by increased in vitro oxygen uptake rates (MO2) of specific tissues, indicating that the raised basal metabolism was caused, in part, by an increase in oxygen demand of specific tissues. Haematological results indicated an increased reliance on anaerobic metabolic pathways in cortisol-treated fish under resting conditions.
    Keywords:  Aerobic scope (AS); Excess postexercise oxygen consumption (EPOC); Maximum metabolic rate (MMR); Metabolic scope (MS); Standard metabolic rate (SMR)
    DOI:  https://doi.org/10.1016/j.cbpa.2021.111098
  94. Toxics. 2021 Oct 11. pii: 258. [Epub ahead of print]9(10):
    Influence of Dietary Compounds on Arsenic Metabolism and Toxicity. Part I-Animal Model Studies.
    Monika Sijko, Lucyna Kozłowska.
      Population and laboratory studies indicate that exposure to various forms of arsenic (As) is associated with many adverse health effects; therefore, methods are being sought out to reduce them. Numerous studies focus on the effects of nutrients on inorganic As (iAs) metabolism and toxicity, mainly in animal models. Therefore, the aim of this review was to analyze the influence of methionine, betaine, choline, folic acid, vitamin B2, B6, B12 and zinc on the efficiency of iAs metabolism and the reduction of the severity of the whole spectrum of disorders related to iAs exposure. In this review, which includes 58 (in vivo and in vitro studies) original papers, we present the current knowledge in the area. In vitro and in vivo animal studies showed that methionine, choline, folic acid, vitamin B2, B12 and zinc reduced the adverse effects of exposure to iAs in the gastrointestinal, urinary, lymphatic, circulatory, nervous, and reproductive systems. On the other hand, it was observed that these compounds (methionine, choline, folic acid, vitamin B2, B12 and zinc) may increase iAs metabolism and reduce toxicity, whereas their deficiency or excess may impair iAs metabolism and increase iAs toxicity. Promising results of in vivo and in vitro on animal model studies show the possibility of using these nutrients in populations particularly exposed to As.
    Keywords:  detoxification; exposure; inorganic arsenic; metal toxicity; methylation; minerals; vitamins
    DOI:  https://doi.org/10.3390/toxics9100258
  95. Adv Exp Med Biol. 2021 ;1329 35-49
    Dormancy in the Tumor Microenvironment.
    Tolu Omokehinde, Rachelle W Johnson.
      Tumor cells frequently disseminate to distant organ sites, where they encounter permissive or restrictive environments that enable them to grow and colonize or enter a dormant state. Tumor dormancy is not strictly defined, but generally describes a tumor cell that is non-proliferative or in a state of balanced equilibrium, in which the proliferation rate of the tumor cell or cells is equal to its rate of cell death. The mechanisms that regulate tumor cell entry into and exit from dormancy are poorly understood, but microenvironmental features as well as tumor cell intrinsic factors play an important role in mediating this transition. Upon homing to distant metastatic sites, tumor cells may disseminate into various niches, most frequently the perivascular, hematopoietic stem cell, or endosteal/osteogenic niche. Tumor cells sense the cytokines, growth factors, and chemo-attractants from each of these niches, and tumor cell expression of cognate ligands and receptors can determine whether a tumor cell enters or exits dormancy. In addition to the secreted factors and cell-cell interactions that regulate dormancy, the cellular milieu also impacts upon disseminated tumor cells to promote or restrain their growth in distant metastatic sites. In this chapter we will discuss the role of the osteogenic and perivascular niche on dormant tumor cells, as well as the impact of hypoxia (low oxygen tensions) and the immune system on the restriction and outgrowth of dormant, disseminated tumor cells.
    Keywords:  Angiogenesis; Cytokines; Dissemination; Dormancy; Endosteal niche; Equilibrium; Growth factors; Hematopoietic stem cell; Hypoxia; Immune system; Immunologic dormancy; Inflammation; Osteogenic niche; Perivascular niche; Tumor dormancy
    DOI:  https://doi.org/10.1007/978-3-030-73119-9_2
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