bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–11–14
72 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Unfolding the role of autophagy in the cancer metabolism.
  2. The biological role of metabolic reprogramming in pancreatic cancer.
  3. Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers.
  4. Lipid metabolism in cancer progression and therapeutic strategies.
  5. Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison.
  6. Molecular aspects of pancreatic cancer: focus on reprogrammed metabolism in a nutrient-deficient environment and potential therapeutic targets.
  7. Pancreatic cancer and adaptive metabolism in a nutrient-deficient environment.
  8. The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment.
  9. Targeting the Redox Imbalance in Mitochondria: A revolutionary mode for cancer therapy.
  10. Metabolism in tumor microenvironment: Implications for cancer immunotherapy.
  11. Metabolic therapy and bioenergetic analysis: the missing piece of the puzzle.
  12. Role of Energy Metabolism in the Progression of Neuroblastoma.
  13. Citrate Promotes Excessive Lipid Biosynthesis and Senescence in Tumor Cells for Tumor Therapy.
  14. The p53 family member p73 in the regulation of cell stress response.
  15. Diverse roles of bitter melon (Momordica charantia) in prevention of oral cancer.
  16. Molecular alterations that precede the establishment of the hallmarks of cancer: An approach on the prevention of hepatocarcinogenesis.
  17. Cyanobacteria derived compounds: Emerging drugs for cancer management.
  18. The role of ferroptosis in lung cancer.
  19. Bisphenol A Alters the Energy Metabolism of Stromal Cells and Could Promote Bladder Cancer Progression.
  20. Role and Function of O-GlcNAcylation in Cancer.
  21. Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming.
  22. Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways.
  23. Nanocatalyst-Mediated Chemodynamic Tumor Therapy.
  24. Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment.
  25. Comprehensive review on signaling pathways of dietary saponins in cancer cells suppression.
  26. Development of simultaneous quantitative analysis of tricarboxylic acid cycle metabolites to identify specific metabolites in cancer cells by targeted metabolomic approach.
  27. The Role of Vitamin D in Gastrointestinal Diseases: Inflammation, Gastric Cancer, and Colorectal Cancer.
  28. Antitumor Effects of Selenium.
  29. Unravelling the Anticancer Mechanisms of Traditional Herbal Medicines with Metabolomics.
  30. Ginsenoside (20S)-protopanaxatriol induces non-protective autophagy and apoptosis by inhibiting Akt/mTOR signaling pathway in triple-negative breast cancer cells.
  31. Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma.
  32. Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core-Shell-Radiosensitizer for Breast Cancer Therapy.
  33. Dynamic regulation of mitochondrial pyruvate metabolism is necessary for orthotopic pancreatic tumor growth.
  34. Stress responses as master keys to epigenomic changes in transcriptome and metabolome for cancer etiology and therapeutics.
  35. Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities.
  36. Gallic Acid: A Potential Anti-Cancer Agent.
  37. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer.
  38. Regulation of cell death mechanisms by melatonin: implications to cancer therapy.
  39. Metabolic Transporters in the Peripheral Nerve-What, Where, and Why?
  40. A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer.
  41. Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment.
  42. Triangulating the pharmacological properties of thymoquinone in regulating reactive oxygen species, inflammation, and cancer: Therapeutic applications and mechanistic pathways.
  43. RGD engineered dendrimer nanotherapeutic as an emerging targeted approach in cancer therapy.
  44. Role of PKM2-Mediated Immunometabolic Reprogramming on Development of Cytokine Storm.
  45. Pyrroloquinoline quinone alleviates oxidative damage induced by high glucose in HepG2 cells.
  46. The nervous system: Orchestra conductor in cancer, regeneration, inflammation and immunity.
  47. Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1.
  48. Phototoxicity of two positive-charged diaryl porphyrins in multicellular tumor spheroids.
  49. Bioactive Cationic Peptides as Potential Agents for Breast Cancer Treatment.
  50. Histone modifications and their role in epigenetics of cancer.
  51. Heparin-Coated Photosensitive Metal-Organic Frameworks as Drug Delivery Nanoplatforms of Autophagy Inhibitors for Sensitized Photodynamic Therapy against Breast Cancer.
  52. Evolutionary metabolic landscape from preneoplasia to invasive lung adenocarcinoma.
  53. Progress of Phototherapy Applications in the Treatment of Bone Cancer.
  54. ROS-Activated homodimeric podophyllotoxin nanomedicine with self-accelerating drug release for efficient cancer eradication.
  55. Current Status of Photodynamic Technology for Urothelial Cancer.
  56. Cysteine Restriction in Murine L929 Fibroblasts as an Alternative Strategy to Methionine Restriction in Cancer Therapy.
  57. Nanofibrous drug delivery systems for breast cancer: a review.
  58. Dissecting in vivo and in vitro redox responses using chemogenetics.
  59. Low-protein diet applied as part of combination therapy or stand-alone normalizes lifespan and tumor proliferation in a model of intestinal cancer.
  60. Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies.
  61. Estrogens and the regulation of glucose metabolism.
  62. Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC.
  63. Personalized nutrition for dementia prevention.
  64. Regulation of NAD+ metabolism in aging and disease.
  65. Bcl-2 Modulation in p53 Signaling Pathway by Flavonoids: A Potential Strategy towards the Treatment of Cancer.
  66. Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment.
  67. Stimuli-responsive charge-reversal MOF@polymer hybrid nanocomposites for enhanced co-delivery of chemotherapeutics towards combination therapy of multidrug-resistant cancer.
  68. Role of purinergic system and vitamin D in the anti-cancer immune response.
  69. Green Synthesis of Gold Nanoparticles Using Plant Extracts as Beneficial Prospect for Cancer Theranostics.
  70. Tree Turmeric: A Super Food and Contemporary Nutraceutical of 21st Century - A Laconic Review.
  71. Mufangji Decoction and Its Active Ingredient Patchouli Alcohol Inhibit Tumor Growth through Regulating Akt/mTOR-Mediated Autophagy in Nonsmall-Cell Lung Cancer.
  72. Delphinidin and Its Glycosides' War on Cancer: Preclinical Perspectives.
  1. Biochem Biophys Rep. 2021 Dec;28 101158
    Unfolding the role of autophagy in the cancer metabolism.
    Anchala Pandey, Pooja Yadav, Sanjeev Shukla.
      Autophagy is considered an indispensable process that scavenges toxins, recycles complex macromolecules, and sustains the essential cellular functions. In addition to its housekeeping role, autophagy plays a substantial role in many pathophysiological processes such as cancer. Certainly, it adapts cancer cells to thrive in the stress conditions such as hypoxia and starvation. Cancer cells indeed have also evolved by exploiting the autophagy process to fulfill energy requirements through the production of metabolic fuel sources and fundamentally altered metabolic pathways. Occasionally autophagy as a foe impedes tumorigenesis and promotes cell death. The complex role of autophagy in cancer makes it a potent therapeutic target and has been actively tested in clinical trials. Moreover, the versatility of autophagy has opened new avenues of effective combinatorial therapeutic strategies. Thereby, it is imperative to comprehend the specificity of autophagy in cancer-metabolism. This review summarizes the recent research and conceptual framework on the regulation of autophagy by various metabolic pathways, enzymes, and their cross-talk in the cancer milieu, including the implementation of altered metabolism and autophagy in clinically approved and experimental therapeutics.
    Keywords:  Autophagy; Cancer; Hypoxia; Metabolism; Starvation; Therapeutics
    DOI:  https://doi.org/10.1016/j.bbrep.2021.101158
  2. MedComm (Beijing). 2020 Dec;1(3): 302-310
    The biological role of metabolic reprogramming in pancreatic cancer.
    Tatsunori Suzuki, Motoyuki Otsuka, Takahiro Seimiya, Takuma Iwata, Takahiro Kishikawa, Kazuhiko Koike.
      Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease and highly resistant to all forms of therapy. PDAC cells reprogram their metabolism extensively to promote their survival and growth. Reflecting the vital role of altered metabolism, experimental and clinical trials targeting the rewired metabolism are currently underway. In this review, we summarize the vital role of metabolic reprogramming in the development of PDAC and the future of novel therapeutic applications.
    Keywords:  autophagy; macropinocytosis; metabolism; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.37
  3. Front Oncol. 2021 ;11 757323
    Alternative Energy: Breaking Down the Diverse Metabolic Features of Lung Cancers.
    Kasey R Cargill, William L Hasken, Carl M Gay, Lauren A Byers.
      Metabolic reprogramming is a hallmark of cancer initiation, progression, and relapse. From the initial observation that cancer cells preferentially ferment glucose to lactate, termed the Warburg effect, to emerging evidence indicating that metabolic heterogeneity and mitochondrial metabolism are also important for tumor growth, the complex mechanisms driving cancer metabolism remain vastly unknown. These unique shifts in metabolism must be further investigated in order to identify unique therapeutic targets for individuals afflicted by this aggressive disease. Although novel therapies have been developed to target metabolic vulnerabilities in a variety of cancer models, only limited efficacy has been achieved. In particular, lung cancer metabolism has remained relatively understudied and underutilized for the advancement of therapeutic strategies, however recent evidence suggests that lung cancers have unique metabolic preferences of their own. This review aims to provide an overview of essential metabolic mechanisms and potential therapeutic agents in order to increase evidence of targeted metabolic inhibition for the treatment of lung cancer, where novel therapeutics are desperately needed.
    Keywords:  glycolysis (Warburg effect); lung cancer; metabolic inhibitors; metabolism; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fonc.2021.757323
  4. MedComm (Beijing). 2021 Mar;2(1): 27-59
    Lipid metabolism in cancer progression and therapeutic strategies.
    Yan Fu, Tiantian Zou, Xiaotian Shen, Peter J Nelson, Jiahui Li, Chao Wu, Jimeng Yang, Yan Zheng, Christiane Bruns, Yue Zhao, Lunxiu Qin, Qiongzhu Dong.
      Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune-associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.
    Keywords:  cancer; lipid metabolism; mechanism; microenvironment; therapeutic strategy
    DOI:  https://doi.org/10.1002/mco2.27
  5. Cancers (Basel). 2021 Oct 31. pii: 5484. [Epub ahead of print]13(21):
    Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison.
    Serena Castelli, Pamela De Falco, Fabio Ciccarone, Enrico Desideri, Maria Rosa Ciriolo.
      Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.
    Keywords:  fatty acid oxidation; lipid catabolism; mitochondrial metabolism; reactive oxygen species
    DOI:  https://doi.org/10.3390/cancers13215484
  6. Cent Eur J Immunol. 2021 ;46(2): 258-263
    Molecular aspects of pancreatic cancer: focus on reprogrammed metabolism in a nutrient-deficient environment and potential therapeutic targets.
    Robert Słotwiński, Gustaw Lech, Sylwia Małgorzata Słotwińska.
      Pancreatic ductal adenocarcinoma (PDAC) is still burdened with high mortality (5-year survival rate < 9%) due to late diagnosis, aggressiveness, and a lack of more effective treatment methods. Early diagnosis and new therapeutic approaches based on the reprogrammed metabolism of the tumor in a nutrient-deficient environment are expected to improve the future treatment of PDAC patients. Research results suggest that genetic and metabolic disorders may precede the onset of neoplastic changes, which should allow for earlier appropriate treatment. Glycolysis and glutaminolysis are the most investigated pathways associated with the highest aggressiveness of pancreatic tumors. Blocking of selected metabolic pathways related to the local adaptive metabolic activity of pancreatic cancer cells improving nutrient acquisition and metabolic crosstalk within the microenvironment to sustain proliferation may inhibit cancer development, increase cancer cells death, and increase sensitivity to other forms of treatment (e.g., chemotherapy). Depriving cancer cells of important nutrients (glucose, glutamine) revealed tumor "checkpoints" for the mechanisms that drive cell proliferation and metastasis formation in order to determine its accuracy for individualization of the therapeutic approach. The present review highlights selected metabolic signaling pathways and their regulators aimed at inhibiting the neoplastic process. Particular attention has been paid to the adaptive metabolism of pancreatic cancer, which promotes its development in an oxygen-deficient and nutrient-poor environment.
    Keywords:  pancreatic carcinoma; reprogrammed metabolism; therapeutic targets
    DOI:  https://doi.org/10.5114/ceji.2021.107027
  7. Cent Eur J Immunol. 2021 ;46(3): 388-394
    Pancreatic cancer and adaptive metabolism in a nutrient-deficient environment.
    Robert Słotwiński, Sylwia Małgorzata Słotwińska.
      Despite tremendous progress in the treatment of many cancer types, leading to a significant increase in survival, pancreatic ductal adenocarcinoma (PDAC) is still burdened with high mortality rates (5-year survival rate < 9%) due to late diagnosis, aggressiveness, and a lack of more effective treatment methods. Early diagnosis and new therapeutic approaches based on the adaptive metabolism of the tumor in a nutrient-deficient environment are expected to improve the future treatment of PDAC patients. It was found that blocking selected metabolic pathways related to the local adaptive metabolic activity of pancreatic cancer cells, improving nutrient acquisition and metabolic crosstalk within the microenvironment to sustain proliferation, may inhibit cancer development, increase cancer cell death, and increase sensitivity to other forms of treatment (e.g., chemotherapy). The present review highlights selected metabolic signaling pathways and their regulators aimed at inhibiting the neoplastic process. Particular attention is paid to the adaptive metabolism of pancreatic cancer, including fatty acids, autophagy, macropinocytosis, and deregulated cell-surface glycoproteins, which promotes cancer cell development in an oxygen-deficient and nutrient-poor environment.
    Keywords:  adaptive metabolism; autophagy; macropinocytosis; mucins; pancreatic carcinoma
    DOI:  https://doi.org/10.5114/ceji.2021.109693
  8. Cancers (Basel). 2021 Oct 29. pii: 5447. [Epub ahead of print]13(21):
    The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment.
    Maria Iorio, Nikkitha Umesh Ganesh, Monica De Luise, Anna Maria Porcelli, Giuseppe Gasparre, Ivana Kurelac.
      Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which cancer cells coexist and interact with several types of microenvironment populations, including endothelial cells, fibroblasts and immune cells. We are just starting to understand how such populations are affected by the metabolic changes occurring in a transformed cell and little is known about the impact of metabolism-targeting drugs on the non-malignant tumor components. Here we provide a general overview of the links between cancer cell metabolism and tumor microenvironment (TME), particularly focusing on the emerging literature reporting TME-specific effects of metabolic therapies.
    Keywords:  cancer metabolism; cancer-associated fibroblasts; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/cancers13215447
  9. Mitochondrion. 2021 Nov 07. pii: S1567-7249(21)00152-5. [Epub ahead of print]
    Targeting the Redox Imbalance in Mitochondria: A revolutionary mode for cancer therapy.
    Shalini Mani, Geeta Swargiary, Stephen J Ralph.
      Changes in reactive oxygen species (ROS) levels affect many aspects of cell behavior. During carcinogenesis, moderate ROS production modifies gene expression to alter cell function, elevating metabolic activity and ROS. To avoid extreme ROS-activated death, cancer cells increase antioxidative capacity, regulating sustained ROS levels that promote growth. Anticancer therapies are exploring inducing supranormal, cytotoxic oxidative stress levels either inhibiting antioxidative capacity or promoting excess ROS to selectively destroy cancer cells, triggering mechanisms such as apoptosis, autophagy, necrosis, or ferroptosis. This review exemplifies pro-oxidants (natural/synthetic/repurposed drugs) and their clinical significance as cancer therapies providing revolutionary approaches.
    Keywords:  Mitochondria; cancer; oxidative stress; pro-oxidants; redox imbalance
    DOI:  https://doi.org/10.1016/j.mito.2021.11.002
  10. MedComm (Beijing). 2020 Jun;1(1): 47-68
    Metabolism in tumor microenvironment: Implications for cancer immunotherapy.
    Rongchen Shi, Yi-Quan Tang, Hongming Miao.
      Tumor microenvironment is a special environment for tumor survival, which is characterized by hypoxia, acidity, nutrient deficiency, and immunosuppression. The environment consists of the vasculature, immune cells, extracellular matrix, and proteins or metabolic molecules. A large number of recent studies have shown that not only tumor cells but also the immune cells in the tumor microenvironment have undergone metabolic reprogramming, which is closely related to tumor drug resistance and malignant progression. Tumor immunotherapy based on T cells gives patients new hope, but faces the dilemma of low response rate. New strategies sensitizing cancer immunotherapy are urgently needed. Metabolic reprogramming can directly affect the biological activity of tumor cells and also regulate the differentiation and activation of immune cells. The authors aim to review the characteristics of tumor microenvironment, the metabolic changes of tumor-associated immune cells, and the regulatory role of metabolic reprogramming in cancer immunotherapy.
    Keywords:  cancer therapy; immunity; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.6
  11. Mol Metab. 2021 Nov 05. pii: S2212-8778(21)00240-4. [Epub ahead of print] 101389
    Metabolic therapy and bioenergetic analysis: the missing piece of the puzzle.
    Tomás Duraj, Josefa Carrión-Navarro, Thomas N Seyfried, Noemí García-Romero, Angel Ayuso-Sacido.
       BACKGROUND: Aberrant metabolism is recognized as a hallmark of cancer, a pillar necessary for proliferation. Regarding bioenergetics (ATP-generation), most cancers display a preference towards aerobic glycolysis ("Warburg effect") and glutaminolysis (mitochondrial substrate level-phosphorylation), but also other metabolites such as lactate, pyruvate, and fat-derived sources. These secondary metabolites can assist in proliferation but cannot fully cover ATP demands.
    SCOPE OF REVIEW: The concept of a static metabolic profile is challenged by instances of heterogeneity and flexibility to meet fuel/anaplerotic demands. Although metabolic therapies are a promising tool to improve therapeutic outcomes, either via pharmacological targets or press-pulse interventions, metabolic plasticity is rarely considered. Lack of bioenergetic analysis in vitro and patient-derived models is hindering translational potential. Here, we review the bioenergetics of cancer and propose a simple analysis of major metabolic pathways, encompassing both affordable and advanced techniques. A comprehensive compendium of Seahorse XF bioenergetic measurements is presented for the first time.
    MAJOR CONCLUSIONS: Standardization of principal readouts might help researchers collect a complete metabolic picture of cancer using the most appropriate methods depending on the sample of interest.
    Keywords:  Cancer; Energy Metabolism; Glycolysis; Oxidative Phosphorylation; Research Design
    DOI:  https://doi.org/10.1016/j.molmet.2021.101389
  12. Int J Mol Sci. 2021 Oct 22. pii: 11421. [Epub ahead of print]22(21):
    Role of Energy Metabolism in the Progression of Neuroblastoma.
    Monika Sakowicz-Burkiewicz, Tadeusz Pawełczyk, Marlena Zyśk.
      Neuroblastoma is a common childhood cancer possessing a significant risk of death. This solid tumor manifests variable clinical behaviors ranging from spontaneous regression to widespread metastatic disease. The lack of promising treatments calls for new research approaches which can enhance the understanding of the molecular background of neuroblastoma. The high proliferation of malignant neuroblastoma cells requires efficient energy metabolism. Thus, we focus our attention on energy pathways and their role in neuroblastoma tumorigenesis. Recent studies suggest that neuroblastoma-driven extracellular vesicles stimulate tumorigenesis inside the recipient cells. Furthermore, proteomic studies have demonstrated extracellular vesicles (EVs) to cargo metabolic enzymes needed to build up a fully operative energy metabolism network. The majority of EV-derived enzymes comes from glycolysis, while other metabolic enzymes have a fatty acid β-oxidation and tricarboxylic acid cycle origin. The previously mentioned glycolysis has been shown to play a primary role in neuroblastoma energy metabolism. Therefore, another way to modify the energy metabolism in neuroblastoma is linked with genetic alterations resulting in the decreased activity of some tricarboxylic acid cycle enzymes and enhanced glycolysis. This metabolic shift enables malignant cells to cope with increasing metabolic stress, nutrition breakdown and an upregulated proliferation ratio.
    Keywords:  extracellular vesicles; glycolysis; neuroblastoma
    DOI:  https://doi.org/10.3390/ijms222111421
  13. Adv Sci (Weinh). 2021 Nov 07. e2101553
    Citrate Promotes Excessive Lipid Biosynthesis and Senescence in Tumor Cells for Tumor Therapy.
    Yangjing Zhao, Xia Liu, Fusheng Si, Lan Huang, Aiqin Gao, Wenli Lin, Daniel F Hoft, Qixiang Shao, Guangyong Peng.
      Metabolic disorder is one of the hallmarks of cancers, and reprogramming of metabolism is becoming a novel strategy for cancer treatment. Citrate is a key metabolite and critical metabolic regulator linking glycolysis and lipid metabolism in cellular energy homeostasis. Here it is reported that citrate treatment (both sodium citrate and citric acid) significantly suppresses tumor cell proliferation and growth in various tumor types. Mechanistically, citrate promotes excessive lipid biosynthesis and induces disruption of lipid metabolism in tumor cells, resulting in tumor cell senescence and growth inhibition. Furthermore, ATM-associated DNA damage response cooperates with MAPK and mTOR signaling pathways to control citrate-induced tumor cell growth arrest and senescence. In vivo studies further demonstrate that citrate administration dramatically inhibits tumor growth and progression in a colon cancer xenograft model. Importantly, citrate administration combined with the conventional chemotherapy drugs exhibits synergistic antitumor effects in vivo in the colon cancer models. These results clearly indicate that citrate can reprogram lipid metabolism and cell fate in cancer cells, and targeting citrate can be a promising therapeutic strategy for tumor treatment.
    Keywords:  DNA damage response; MAPK; apoptosis; cellular senescence; chemotherapy; citrate; lipid metabolism; mTOR
    DOI:  https://doi.org/10.1002/advs.202101553
  14. Biol Direct. 2021 Nov 08. 16(1): 23
    The p53 family member p73 in the regulation of cell stress response.
    Julian M Rozenberg, Svetlana Zvereva, Aleksandra Dalina, Igor Blatov, Ilya Zubarev, Daniil Luppov, Alexander Bessmertnyi, Alexander Romanishin, Lamak Alsoulaiman, Vadim Kumeiko, Alexander Kagansky, Gerry Melino, Carlo Ganini, Nikolai A Barlev.
      During oncogenesis, cells become unrestrictedly proliferative thereby altering the tissue homeostasis and resulting in subsequent hyperplasia. This process is paralleled by resumption of cell cycle, aberrant DNA repair and blunting the apoptotic program in response to DNA damage. In most human cancers these processes are associated with malfunctioning of tumor suppressor p53. Intriguingly, in some cases two other members of the p53 family of proteins, transcription factors p63 and p73, can compensate for loss of p53. Although both p63 and p73 can bind the same DNA sequences as p53 and their transcriptionally active isoforms are able to regulate the expression of p53-dependent genes, the strongest overlap with p53 functions was detected for p73. Surprisingly, unlike p53, the p73 is rarely lost or mutated in cancers. On the contrary, its inactive isoforms are often overexpressed in cancer. In this review, we discuss several lines of evidence that cancer cells develop various mechanisms to repress p73-mediated cell death. Moreover, p73 isoforms may promote cancer growth by enhancing an anti-oxidative response, the Warburg effect and by repressing senescence. Thus, we speculate that the role of p73 in tumorigenesis can be ambivalent and hence, requires new therapeutic strategies that would specifically repress the oncogenic functions of p73, while keeping its tumor suppressive properties intact.
    Keywords:  Cancer hallmarks; Tumor suppressor p53; p73
    DOI:  https://doi.org/10.1186/s13062-021-00307-5
  15. J Cancer Metastasis Treat. 2021 ;pii: 12. [Epub ahead of print]7
    Diverse roles of bitter melon (Momordica charantia) in prevention of oral cancer.
    Subhayan Sur, Ratna B Ray.
      Oral squamous cell carcinoma (OSCC) is one of the common lethal malignancies which is increasing rapidly in the world. Increasing risks from alcohol and tobacco habits, lack of early detection markers, lack of effective chemotherapeutic agents, recurrence and distant metastasis make the disease more complicated to manage. Laboratory-based studies and epidemiological studies indicate important roles of nutraceuticals to manage different cancers. The plant bitter melon (Momordica charantia) is a good source of nutrients and bio-active phytochemicals such as triterpenoids, triterpene glycosides, phenolic acids, flavonoids, lectins, sterols and proteins. The plant is widely grown in Asia, Africa, and South America. Bitter melon has traditionally been used as a folk medicine and Ayurvedic medicine in Asian culture to treat diseases such as diabetes, since ancient times. The crude extract and some of the isolated pure compounds of bitter melon show potential anticancer effects against different cancers. In this review, we shed light on its effect on OSCC. Bitter melon extract has been found to inhibit cell proliferation and metabolism, induce cell death and enhance the immune defense system in the prevention of OSCC in vitro and in vivo. Thus, bitter melon may be used as an attractive chemopreventive agent in progression towards OSCC clinical study.
    Keywords:  Bitter melon (Momordica charantia); cancer metabolism; cancer prevention; immune system; oral squamous cell carcinoma; signal transduction
    DOI:  https://doi.org/10.20517/2394-4722.2020.126
  16. Biochem Pharmacol. 2021 Oct 30. pii: S0006-2952(21)00434-2. [Epub ahead of print] 114818
    Molecular alterations that precede the establishment of the hallmarks of cancer: An approach on the prevention of hepatocarcinogenesis.
    Brisa Rodope Alarcón-Sánchez, Julio Isael Pérez-Carreón, Saúl Villa-Treviño, Jaime Arellanes-Robledo.
      Chronic liver injury promotes the molecular alterations that precede the establishment of cancer. Usually, several decades of chronic insults are needed to develop the most common primary liver tumor known as hepatocellular carcinoma. As other cancer types, liver cancer cells are governed by a common set of rules collectively called the hallmarks of cancer. Although those rules have provided a conceptual framework for understanding the complex pathophysiology of established tumors, therapeutic options are still ineffective in advanced stages. Thus, the molecular alterations that precede the establishment of cancer remain an attractive target for therapeutic interventions. Here, we first summarize the chemopreventive interventions targeting the early liver carcinogenesis stages. After an integrative analysis on the plethora of molecular alterations regulated by anticancer agents, we then underline and discuss that two critical processes namely oxidative stress and genetic alterations, play the role of 'dirty work laborer' in the initial cell damage and drive the transformation of preneoplastic into neoplastic cells, respectively; besides, the activation of cellular senescence works as a key mechanism in attempting to prevent the onset and establishment of liver cancer. Whereas the detrimental effects of the binomial made up of oxidative stress and genetic alterations are either eliminated or reduced, senescence activation is promoted by anticancer agents. We argue that collectively, oxidative stress, genetic alterations, and senescence are key events that influence the fate of initiated cells and the establishment of the hallmarks of cancer.
    Keywords:  Chemoprevention; Diethylnitrosamine; Genetic alterations; Liver cancer initiation; Oxidative stress; Senescence
    DOI:  https://doi.org/10.1016/j.bcp.2021.114818
  17. J Basic Microbiol. 2021 Nov 08.
    Cyanobacteria derived compounds: Emerging drugs for cancer management.
    Aqsa Shahid, Mohsin Khurshid, Bilal Aslam, Saima Muzammil, Hafiza Mahreen Mehwish, Muhammad Shahid Riaz Rajoka, Hafiz Fakhar Hayat, Muhammad Hassan Sarfraz, Muhammad Khuram Razzaq, Muhammad Atif Nisar, Muhammad Waseem.
      The wide diversity of cyanobacterial species and their role in a variety of biological activities have been reported in the previous few years. Cyanobacteria, especially from marine sources, constitutes a major source of biologically active metabolites that have gained great attention especially due to their anticancer potential. Numerous chemically diverse metabolites from various cyanobacterial species have been recognized to inhibit the growth and progression of tumor cells through the induction of apoptosis in many different types of cancers. These metabolites activate the apoptosis in the cancer cells by different molecular mechanisms, however, the dysregulation of the mitochondrial pathway, death receptors signaling pathways, and the activation of several caspases are the crucial mechanisms that got considerable interest. The array of metabolites and the range of mechanisms involved may also help to overcome the resistance acquired by the different tumor types against the ongoing therapeutic agents. Therefore, the primary or secondary metabolites from the cyanobacteria as well as their synthetic derivates could be used to develop novel anticancer drugs alone or in combination with other chemotherapeutic agents. In this study, we have discussed the role of cyanobacterial metabolites in the induction of cytotoxicity and the potential to inhibit the growth of cancer cells through the induction of apoptosis, cell signaling alteration, oxidative damage, and mitochondrial dysfunctions. Moreover, the various metabolites produced by cyanobacteria have been summarized with their anticancer mechanisms. Furthermore, the ongoing trials and future developments for the therapeutic implications of these compounds in cancer therapy have been discussed.
    Keywords:  anticancer drugs; apoptosis; aquaculture; caspases; metabolomics
    DOI:  https://doi.org/10.1002/jobm.202100459
  18. Biomark Res. 2021 Nov 06. 9(1): 82
    The role of ferroptosis in lung cancer.
    Sikai Wu, Chengchu Zhu, Daolin Tang, Q Ping Dou, Jianfei Shen, Xin Chen.
      Lung cancer is one of the most common cancers in the world. Although medical treatment has made impressive progress in recent years, it is still one of the leading causes of cancer-related deaths in men and women. Ferroptosis is a type of non-apoptotic cell death modality, usually characterized by iron-dependent lipid peroxidation, rather than caspase-induced protein cleavage. Excessive or lack of ferroptosis is associated with a variety of diseases, including cancer and ischaemia-reperfusion injury. Recent preclinical evidence suggests that targeting ferroptotic pathway is a potential strategy for the treatment of lung cancer. In this review, we summarize the core mechanism and regulatory network of ferroptosis in lung cancer cells, and highlight ferroptosis induction-related tumor therapies. The reviewed information may provide new insights for targeted lung cancer therapy.
    Keywords:  Ferroptosis; Lipid peroxidation; Lung cancer; ROS; iron
    DOI:  https://doi.org/10.1186/s40364-021-00338-0
  19. Cancers (Basel). 2021 Oct 30. pii: 5461. [Epub ahead of print]13(21):
    Bisphenol A Alters the Energy Metabolism of Stromal Cells and Could Promote Bladder Cancer Progression.
    Ève Pellerin, Stéphane Chabaud, Frédéric Pouliot, Martin Pelletier, Stéphane Bolduc.
      Bisphenol A (BPA) is an endocrine-disrupting molecule used in plastics. Through its release in food and the environment, BPA can be found in humans and is mostly excreted in urine. The bladder is therefore continuously exposed to this compound. BPA can bind to multiple cell receptors involved in proliferation, migration and invasion pathways, and exposure to BPA is associated with cancer progression. Considering the physiological concentrations of BPA in urine, we tested the effect of nanomolar concentrations of BPA on the metabolism of bladder fibroblasts and cancer-associated fibroblasts (CAFs). Our results show that BPA led to a decreased metabolism in fibroblasts, which could alter the extracellular matrix. Furthermore, CAF induction triggered a metabolic switch, similar to the Warburg effect described in cancer cells. Additionally, we demonstrated that nanomolar concentrations of BPA could exacerbate this metabolic switch observed in CAFs via an increased glycolytic metabolism, leading to greater acidification of the extracellular environment. These findings suggest that chronic exposure to BPA could promote cancer progression through an alteration of the metabolism of stromal cells.
    Keywords:  bisphenol A; bladder cancer; cancer-associated fibroblasts; glycolysis; metabolism
    DOI:  https://doi.org/10.3390/cancers13215461
  20. Cancers (Basel). 2021 Oct 26. pii: 5365. [Epub ahead of print]13(21):
    Role and Function of O-GlcNAcylation in Cancer.
    Jii Bum Lee, Kyoung-Ho Pyo, Hye Ryun Kim.
      Cancer cells are able to reprogram their glucose metabolism and retain energy via glycolysis even under aerobic conditions. They activate the hexosamine biosynthetic pathway (HBP), and the complex interplay of O-linked N-acetylglucosaminylation (O-GlcNAcylation) via deprivation of nutrients or increase in cellular stress results in the proliferation, progression, and metastasis of cancer cells. Notably, cancer is one of the emerging diseases associated with O-GlcNAcylation. In this review, we summarize studies that delineate the role of O-GlcNAcylation in cancer, including its modulation in metastasis, function with receptor tyrosine kinases, and resistance to chemotherapeutic agents, such as cisplatin. In addition, we discuss the function of O-GlcNAcylation in eliciting immune responses associated with immune surveillance in the tumor microenvironment. O-GlcNAcylation is increasingly accepted as one of the key players involved in the activation and differentiation of T cells and macrophages. Finally, we discuss the prognostic role of O-GlcNAcylation and potential therapeutic agents such as O-linked β-N-acetylglucosamine-transferase inhibitors, which may help overcome the resistance mechanism associated with the reprogramming of glucose metabolism.
    Keywords:  O-GlcNAc transferase; O-GlcNAcase; O-GlcNAcylation; cancer; cellular stress; immune surveillance
    DOI:  https://doi.org/10.3390/cancers13215365
  21. Cancer Cell Int. 2021 Nov 07. 21(1): 597
    Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming.
    Tinghao Li, Hang Tong, Hubin Yin, Yi Luo, Junlong Zhu, Zijia Qin, Siwen Yin, Weiyang He.
       BACKGROUND: Aberrant autophagy and preternatural elevated glycolysis are prevalent in bladder cancer (BLCA) and are both related to malignant progression. However, the regulatory relationship between autophagy and glycolytic metabolism remains largely unknown. We imitated starvation conditions in the tumour microenvironment and found significantly increased levels of autophagy and aerobic glycolysis, which both regulated the progression of BLCA cells. We further explored the regulatory relationships and mechanisms between them.
    METHODS: We used immunoblotting, immunofluorescence and transmission electron microscopy to detect autophagy levels in BLCA cells under different treatments. Lactate and glucose concentration detection demonstrated changes in glycolysis. The expression of lactate dehydrogenase A (LDHA) was detected at the transcriptional and translational levels and was also silenced by small interfering RNA, and the effects on malignant progression were further tested. The underlying mechanisms of signalling pathways were evaluated by western blot, immunofluorescence and immunoprecipitation assays.
    RESULTS: Starvation induced autophagy, regulated glycolysis by upregulating the expression of LDHA and caused progressive changes in BLCA cells. Mechanistically, after starvation, the ubiquitination modification of Axin1 increased, and Axin1 combined with P62 was further degraded by the autophagy-lysosome pathway. Liberated β-catenin nuclear translocation increased, binding with LEF1/TCF4 and promoting LDHA transcriptional expression. Additionally, high expression of LDHA was observed in cancer tissues and was positively related to progression.
    CONCLUSION: Our study demonstrated that starvation-induced autophagy modulates glucose metabolic reprogramming by enhancing Axin1 degradation and β-catenin nuclear translocation in BLCA, which promotes the transcriptional expression of LDHA and further malignant progression.
    Keywords:  Autophagy; Axin1; Bladder cancer; Glycolysis; LDHA; Wnt/β-catenin signalling
    DOI:  https://doi.org/10.1186/s12935-021-02303-1
  22. Front Pharmacol. 2021 ;12 710304
    Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways.
    Manuel Humberto Cháirez-Ramírez, Karen Griselda de la Cruz-López, Alejandro García-Carrancá.
      Polyphenols constitute an important group of natural products that are traditionally associated with a wide range of bioactivities. These are usually found in low concentrations in natural products and are now available in nutraceuticals or dietary supplements. A group of polyphenols that include apigenin, quercetin, curcumin, resveratrol, EGCG, and kaempferol have been shown to regulate signaling pathways that are central for cancer development, progression, and metastasis. Here, we describe novel mechanistic insights on the effect of this group of polyphenols on key elements of the signaling pathways impacting cancer. We describe the protein modifications induced by these polyphenols and their effect on the central elements of several signaling pathways including PI3K, Akt, mTOR, RAS, and MAPK and particularly those affecting the tumor suppressor p53 protein. Modifications of p53 induced by these polyphenols regulate p53 gene expression and protein levels and posttranslational modifications such as phosphorylation, acetylation, and ubiquitination that influence stability, subcellular location, activation of new transcriptional targets, and the role of p53 in response to DNA damage, apoptosis control, cell- cycle regulation, senescence, and cell fate. Thus, deep understanding of the effects that polyphenols have on these key players in cancer-driving signaling pathways will certainly lead to better designed targeted therapies, with less toxicity for cancer treatment. The scope of this review centers on the regulation of key elements of cancer signaling pathways by the most studied polyphenols and highlights the importance of a profound understanding of these regulations in order to improve cancer treatment and control with natural products.
    Keywords:  MAPK; PI3K-AKT pathway; RAS; cancer; p53; polyphenols; signaling pathways
    DOI:  https://doi.org/10.3389/fphar.2021.710304
  23. Adv Healthc Mater. 2021 Nov 09. e2101971
    Nanocatalyst-Mediated Chemodynamic Tumor Therapy.
    Lu Zhang, Chu-Xin Li, Shuang-Shuang Wan, Xian-Zheng Zhang.
      Traditional tumor treatments, including chemotherapy, radiotherapy, photodynamic therapy, and photothermal therapy, have been developed and used to treat different types of cancer. Recently, chemodynamic therapy (CDT) has been emerged as a novel cancer therapeutic strategy. CDT utilizes Fenton or Fenton-like reaction to generate highly cytotoxic hydroxyl radicals (·OH) from endogenous hydrogen peroxide (H2 O2 ) to kill cancer cells, which displays promising therapeutic potentials for tumor treatment. However, the low catalytic efficiency and off-target side effects of Fenton reaction limit the biomedical application of CDT. In this regard, various strategies have been implemented to potentiate CDT against tumor, including retrofitting the tumor microenvironment (e.g., increasing H2 O2 level, decreasing reductive substances, and reducing pH), enhancing the catalytic efficiency of nanocatalysts, and other strategies. This review aims to summarize the development of CDT and summarize these recent progresses of nanocatalyst-mediated CDT for antitumor application. The future development trend and challenges of CDT are also discussed. This article is protected by copyright. All rights reserved.
    Keywords:  Fenton nanocatalyst; chemodynamic therapy; hydroxyl radical; tumor microenvironment; tumor therapy
    DOI:  https://doi.org/10.1002/adhm.202101971
  24. Cancers (Basel). 2021 Oct 28. pii: 5414. [Epub ahead of print]13(21):
    Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment.
    Raquel Muñoz, Alessandra Girotti, Denise Hileeto, Francisco Javier Arias.
      The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.
    Keywords:  bone-marrow-derived cells; cancer therapy; cancer-associated fibroblasts; metronomic chemotherapy; nanocarriers; nanomedicine; tumor microenvironment; tumor vascularization
    DOI:  https://doi.org/10.3390/cancers13215414
  25. Crit Rev Food Sci Nutr. 2021 Nov 09. 1-26
    Comprehensive review on signaling pathways of dietary saponins in cancer cells suppression.
    Yifan Zhou, Ammad Ahmad Farooqi, Baojun Xu.
      Nutrigenomics utilizes high-throughput genomic technologies to reveal changes in gene and protein levels. Excitingly, ever-growing body of scientific findings has provided sufficient evidence about the interplay between diet and genes. Cutting-edge research and advancements in genomics, epigenetics and metabolomics have deepened our understanding on the role of dietary factors in the inhibition of carcinogenesis and metastasis. Dietary saponins, a type of triterpene glycosides, are generally found in Platycodon grandifloras, Dioscorea oppositifolia, asparagus, legumes, and sea cucumber. Wealth of information has started to shed light on pleiotropic mechanistic roles of dietary saponins in cancer prevention and inhibition. In this review, we have attempted to summarize the in vitro research of dietary saponins in the last two decades by searching common databases such as Google Scholar, PubMed, Scopus, and Web of Science. The results showed that dietary saponins exerted anti-cancer activities via regulation of apoptosis, autophagy, arrest cell cycle, anti-proliferation, anti-metastasis, and anti-angiogenesis, by regulation of several critical signaling pathways, including MAPK, PI3K/Akt/mTOR, NF-κB, and VEGF/VEGFR. However, there is no data about the dosage of dietary saponins for practical anti-cancer effects in human bodies. Extensive clinical studies are needed to confirm the effectiveness of dietary saponins for further commercial and medical applications.
    Keywords:  Akt/mTOR; MAPK; NF-κB; VEGFR; anticancer; caspases-cascades; dietary saponin; signaling pathway
    DOI:  https://doi.org/10.1080/10408398.2021.2000933
  26. Biochem Biophys Res Commun. 2021 Nov 05. pii: S0006-291X(21)01495-9. [Epub ahead of print]584 53-59
    Development of simultaneous quantitative analysis of tricarboxylic acid cycle metabolites to identify specific metabolites in cancer cells by targeted metabolomic approach.
    Tetsushi Yamamoto, Kanta Sato, Masafumi Yamaguchi, Kuniko Mitamura, Atsushi Taga.
      The tricarboxylic acid (TCA) cycle is one of the most important pathways of energy metabolism, and the profiles of its components are influenced by factors such as diseases and diets. Therefore, the differences in metabolic profile of TCA cycle between healthy and cancer cells have been the focus of studies to understand pathological conditions. In this study, we developed a quantitative method to measure TCA cycle metabolites using LC-MS/MS to obtain useful metabolic profiles for development of diagnostic and therapeutic methods for cancer. We successfully analyzed 11 TCA cycle metabolites by LC MS/MS with high reproducibility by using a PFP column with 0.5% formic acid as a mobile phase. Next, we analyzed the concentration of TCA cycle metabolites in human cell lines (HaCaT: normal skin keratinocytes; A431: skin squamous carcinoma cells; SW480: colorectal cancer cells). We observed reduced concentration of succinate and increased concentration of citrate, 2-hydroxyglutarate, and glutamine in A431 cells as compared with HaCaT cells. On the other hand, decreased concentration of isocitrate, fumarate, and α-ketoglutarate and increased concentration of malate, glutamine, and glutamate in A431 cells were observed in comparison with SW480 cells. These findings suggested the possibility of identifying disease-specific metabolites and/or organ-specific metabolites by using this targeted metabolomic analysis.
    Keywords:  Cancer; Energy metabolism; LC-MS; TCA cycle; Targeted metabolomics
    DOI:  https://doi.org/10.1016/j.bbrc.2021.10.072
  27. Curr Med Chem. 2021 Nov 11.
    The Role of Vitamin D in Gastrointestinal Diseases: Inflammation, Gastric Cancer, and Colorectal Cancer.
    Yao Chen, Jue Hou, Zhangang Xiao, Yueshui Zhao, Fukuan Du, Xu Wu, Mingxing Li, Yu Chen, Lin Zhang, Chi Hin Cho, Qinglian Wen, Wei Hu, Jing Shen.
      Vitamin D as a prohormone is converted into the active form in vivo and binds to vitamin D receptors, exercising a wide range of biological functions. Recent studies strongly support that vitamin D supplementation is associated with reduced cancer risk and a good prognosis. Gastrointestinal cancer is the leading cause of cancer-related deaths worldwide. The key role of vitamin D in the development of gastrointestinal cancer has been observed. Moreover, Vitamin D can also affect innate immunity and perform anti-inflammation and anti-infection actions. Given the intimate relationship between cancer and inflammation, we herein summarize epidemiological and preclinical studies of vitamin D and the underlying mechanism of its action in inflammation, gastric and colorectal cancer by our group and other researchers. A beneficial effect of vitamin D in cancer and inflammatory disease has been supported by different studies. More controlled and larger clinical trials are needed before a reliable conclusion and realization of vitamin D supplementation in the adjunct treatment of gastrointestinal inflammation and cancer.
    Keywords:  Antimicrobial peptide; Gastrointestinal cancer; Inflammation; Innate immunity; Metabolism; Vitamin D
    DOI:  https://doi.org/10.2174/0929867328666211111163304
  28. Int J Mol Sci. 2021 Oct 31. pii: 11844. [Epub ahead of print]22(21):
    Antitumor Effects of Selenium.
    Seung Jo Kim, Min Chul Choi, Jong Min Park, An Sik Chung.
      Functions of selenium are diverse as antioxidant, anti-inflammation, increased immunity, reduced cancer incidence, blocking tumor invasion and metastasis, and further clinical application as treatment with radiation and chemotherapy. These functions of selenium are mostly related to oxidation and reduction mechanisms of selenium metabolites. Hydrogen selenide from selenite, and methylselenol (MSeH) from Se-methylselenocyteine (MSeC) and methylseleninicacid (MSeA) are the most reactive metabolites produced reactive oxygen species (ROS); furthermore, these metabolites may involve in oxidizing sulfhydryl groups, including glutathione. Selenite also reacted with glutathione and produces hydrogen selenide via selenodiglutathione (SeDG), which induces cytotoxicity as cell apoptosis, ROS production, DNA damage, and adenosine-methionine methylation in the cellular nucleus. However, a more pronounced effect was shown in the subsequent treatment of sodium selenite with chemotherapy and radiation therapy. High doses of sodium selenite were effective to increase radiation therapy and chemotherapy, and further to reduce radiation side effects and drug resistance. In our study, advanced cancer patients can tolerate until 5000 μg of sodium selenite in combination with radiation and chemotherapy since the half-life of sodium selenite may be relatively short, and, further, selenium may accumulates more in cancer cells than that of normal cells, which may be toxic to the cancer cells. Further clinical studies of high amount sodium selenite are required to treat advanced cancer patients.
    Keywords:  ROS; apoptosis; metastasis; selenium compounds; treatment of advanced cancer patients
    DOI:  https://doi.org/10.3390/ijms222111844
  29. Molecules. 2021 Oct 29. pii: 6541. [Epub ahead of print]26(21):
    Unravelling the Anticancer Mechanisms of Traditional Herbal Medicines with Metabolomics.
    Omolola R Oyenihi, Ayodeji B Oyenihi, Joseph O Erhabor, Motlalepula G Matsabisa, Oluwafemi O Oguntibeju.
      Metabolite profiling of cancer cells presents many opportunities for anticancer drug discovery. The Chinese, Indian, and African flora, in particular, offers a diverse source of anticancer therapeutics as documented in traditional folklores. In-depth scientific information relating to mechanisms of action, quality control, and safety profile will promote their extensive usage in cancer therapy. Metabolomics may be a more holistic strategy to gain valuable insights into the anticancer mechanisms of action of plants but this has remained largely unexplored. This review, therefore, presents the available metabolomics studies on the anticancer effects of herbal medicines commonly used in Africa and Asia. In addition, we present some scientifically understudied 'candidate plants' for cancer metabolomics studies and highlight the relevance of metabolomics in addressing other challenges facing the drug development of anticancer herbs. Finally, we discussed the challenges of using metabolomics to uncover the underlying mechanisms of potential anticancer herbs and the progress made in this regard.
    Keywords:  cancer; herb; metabolic reprogramming; metabolomics; phytomedicine
    DOI:  https://doi.org/10.3390/molecules26216541
  30. Biochem Biophys Res Commun. 2021 Nov 02. pii: S0006-291X(21)01483-2. [Epub ahead of print]583 184-191
    Ginsenoside (20S)-protopanaxatriol induces non-protective autophagy and apoptosis by inhibiting Akt/mTOR signaling pathway in triple-negative breast cancer cells.
    Yan Li, Panpan Wang, Zhuoling Zou, Qi Pan, Xiaoyun Li, Zien Liang, Lingyu Li, Yingbing Lin, Xueyu Peng, Ronghua Zhang, Huaqin Tian, Li Han.
      Triple-negative breast cancer (TNBC) lacks a recognized therapeutic molecular target and has an unfavorable prognosis. (20S)-Protopanaxatriol (g-PPT, PPT) is an active metabolite extracted from ginseng. Accumulating evidence suggests that it has good anti-cancer activity in vivo and in vitro. In this study, we aimed to elucidate the anti-tumor effects of PPT in TNBC cells and tumor-bearing mice, as well as the relevant molecular mechanisms of autophagy and apoptosis. In vitro, we have found that PPT is capable of inducing non-protective autophagy and apoptosis, thus exerting some anti-proliferative and anti-migration activity in TNBC cells. And in vivo, the therapeutic effects of PPT were evaluated by xenograft mouse models. The potential binding mode of PPT and Akt was predicted by molecular docking. Our findings indicated that PPT treatment induced non-protective autophagy in TNBC cells by inhibiting the Akt/mTOR signaling pathway. Therefore, PPT may be a potential treatment for TNBC in the future.
    Keywords:  (20S)-Protopanaxatriol; Akt/mTOR signaling pathway; Apoptosis; Autophagy; Triple negative breast cancer (TNBC)
    DOI:  https://doi.org/10.1016/j.bbrc.2021.10.067
  31. Oncogene. 2021 Nov 11.
    Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma.
    Gabriel Alzial, Ophelie Renoult, François Paris, Catherine Gratas, Anne Clavreul, Claire Pecqueur.
      Brain tumors actively reprogram their cellular metabolism to survive and proliferate, thus offering potential therapeutic opportunities. Over the past decade, extensive research has been done on mutant IDH enzymes as markers of good prognosis in glioblastoma, a highly aggressive brain tumor in adults with dismal prognosis. Yet, 95% of glioblastoma are IDH wild-type. Here, we review current knowledge about IDH wild-type enzymes and their putative role in mechanisms driving tumor progression. After a brief overview on tumor metabolic adaptation, we present the diverse metabolic function of IDH enzymes and their roles in glioblastoma initiation, progression and response to treatments. Finally, we will discuss wild-type IDH targeting in primary glioblastoma.
    DOI:  https://doi.org/10.1038/s41388-021-02056-1
  32. Cancers (Basel). 2021 Nov 07. pii: 5571. [Epub ahead of print]13(21):
    Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core-Shell-Radiosensitizer for Breast Cancer Therapy.
    Mostafa A Askar, Noura M Thabet, Gharieb S El-Sayyad, Ahmed I El-Batal, Mohamed Abd Elkodous, Omama E El Shawi, Hamed Helal, Mohamed K Abdel-Rafei.
      Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels proliferation and progression. Due to the late manifestation of symptoms, rigorous treatment regimens are required following diagnosis. Existing treatments are limited by a lack of specificity, systemic toxicity, temporary remission, and radio-resistance in BC. In this study, we have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This composed of hyaluronic acid (HA) and folic acid (FA) conjugated to a 2-deoxy glucose (2DG) shell linked to a layer of dichloroacetate (DCA) and a magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective BC treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy were thoroughly examined. Mechanistically, we identified multiple component signaling pathways as important regulators of BC metabolism and mediators for the inhibitory effects elicited by DDM. Nanoparticles exhibited sustained DDM release properties in a bio-relevant media, which was responsive to the acidic pH enabling eligibility to the control of drug release from nanoparticles. DDM-loaded and HA-FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays revealed that the functionalized DDM significantly suppressed cancer cell growth and improved radiotherapy (RT) through inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our data suggest that glycolytic and OXPHOS pathway modulation occurs via the PI3K/AKT/mTOR/NF-κB/VEGFlow and P53high signaling pathway. In conclusion, the multi-functionalized DDM opposed tumor-associated metabolic reprogramming via multiple signaling pathways in BC cells as a promising targeted metabolic approach.
    Keywords:  antitumor; breast cancer; multifunctional core–shell nanoparticles; radio-sensitization; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13215571
  33. Cancer Metab. 2021 Nov 08. 9(1): 39
    Dynamic regulation of mitochondrial pyruvate metabolism is necessary for orthotopic pancreatic tumor growth.
    Nancy P Echeverri Ruiz, Vijay Mohan, Jinghai Wu, Sabina Scott, McKenzie Kreamer, Martin Benej, Tereza Golias, Ioanna Papandreou, Nicholas C Denko.
       BACKGROUND: Pyruvate dehydrogenase complex (PDC) plays a central role in carbohydrate metabolism, linking cytoplasmic glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle. PDC is a conserved E1-E2-E3 dehydrogenase with a PDHA1 and PDHB heterotetramer functioning as the E1 subunit. PDHA1 contains three serine residues that can be reversibly phosphorylated by a dedicated family of four inhibitory pyruvate dehydrogenase kinases (PDHK1-4) and two reactivating phosphatases (PDP1, 2). Hypoxia induces the expression of PDHK1 and PDHK3 and hyperphosphorylates PDHA1. The role of PDC in metabolic reprogramming and tumor progression appears to be for the integration of oncogenic and environmental signals which supports tumor growth.
    METHODS: To isolate the function of the serine-dependent regulation of PDC, we engineered MiaPaca2 cells to express PDHA1 protein with either intact serines at positions 232, 293, and 300 or all the combinations of non-phosphorylatable alanine substitution mutations. These lines were compared in vitro for biochemical response to hypoxia by western blot, metabolic activity by biochemical assay and Seahorse XF flux analysis, and growth in media with reduced exogenous metabolites. The lines were also tested for growth in vivo after orthotopic injection into the pancreata of immune-deficient mice.
    RESULTS: In this family of cells with non-phosphorylatable PDHA1, we found reduced hypoxic phosphorylation of PDHA1, decreased PDH enzymatic activity in normoxia and hypoxia, decreased mitochondrial function by Seahorse flux assay, reduced in vitro growth of cells in media depleted of lipids, and reduced growth of tumors after orthotopic transplantation of cells into the pancreata of immune-deficient mice.
    CONCLUSIONS: We found that any substitution of alanine for serine at regulatory sites generated a hypomorphic PDC. However, the reduced PDC activity was insensitive to further reduction in hypoxia. These cells had a very modest reduction of growth in vitro, but failed to grow as tumors indicating that dynamic PDC adaptation to microenvironmental conditions is necessary to support pancreatic cancer growth in vivo.
    Keywords:  Glucose metabolism; Hypoxia; Mitochondria; Orthotopic pancreatic tumors; Pyruvate dehydrogenase
    DOI:  https://doi.org/10.1186/s40170-021-00275-4
  34. Mol Cell Biol. 2021 Nov 08. MCB0048321
    Stress responses as master keys to epigenomic changes in transcriptome and metabolome for cancer etiology and therapeutics.
    Atanu Mondal, Apoorva Bhattacharya, Vipin Singh, Shruti Pandita, Albino Bacolla, Raj K Pandita, John A Tainer, Kenneth S Ramos, Tej K Pandita, Chandrima Das.
      From initiation through progression, cancer cells are subjected to a magnitude of endogenous and exogenous stresses, which aid in their neoplastic transformation. Exposure to these classes of stress induces imbalance in cellular homeostasis and, in response, cancer cells employ informative adaptive mechanisms to rebalance biochemical processes that facilitate survival and maintain their existence. Different kinds of stress stimuli trigger epigenetic alterations in cancer cells, which leads to changes in their transcriptome and metabolome, ultimately resulting in suppression of growth inhibition or induction of apoptosis. Whether cancer cells show a protective response to stress or succumb to cell death depends on the type of stress and duration of exposure. A thorough understanding of epigenetic and molecular architecture of cancer cell stress response pathways can unveil a plethora of information required to develop novel anti-cancer therapeutics. The present view highlights current knowledge about alterations in epigenome and transcriptome of cancer cells as a consequence of exposure to different physicochemical stressful stimuli such as reactive oxygen species (ROS), hypoxia, radiation, hyperthermia, genotoxic agents, and nutrient deprivation. Currently, an anti-cancer treatment scenario involving the imposition of stress on target cancer cells is gaining traction to augment or even replace conventional therapeutic regimens. Therefore, a comprehensive understanding of stress response pathways is crucial for devising and implementing novel therapeutic strategies.
    DOI:  https://doi.org/10.1128/MCB.00483-21
  35. Cancers (Basel). 2021 Oct 31. pii: 5481. [Epub ahead of print]13(21):
    Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities.
    Sapana Bansod, Paarth B Dodhiawala, Kian-Huat Lim.
      Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network.
    Keywords:  IRAK4; MK2; TAK1; TPL2; inflammation; pancreatic cancer; stroma
    DOI:  https://doi.org/10.3390/cancers13215481
  36. Chin J Integr Med. 2021 Nov 10.
    Gallic Acid: A Potential Anti-Cancer Agent.
    Yuan Jiang, Jin Pei, Yan Zheng, Yu-Jing Miao, Bao-Zhong Duan, Lin-Fang Huang.
      Cancer is one of the most devastating diseases worldwide and definitive therapeutics for treating cancer are not yet available despite extensive research efforts. The key challenges include limiting factors connected with traditional chemotherapeutics, primarily drug resistance, low response rates, and adverse side-effects. Therefore, there is a high demand for novel anti-cancer drugs that are both potent and safe for cancer prevention and treatment. Gallic acid (GA), a natural botanic phenolic compound, can mediate various therapeutic properties that are involved in anti-inflammation, anti-obesity, and anti-cancer activities. More recently, GA has been shown to exert anti-cancer activities via several biological pathways that include migration, metastasis, apoptosis, cell cycle arrest, angiogenesis, and oncogene expression. This review discusses two aspects, one is the anti-cancer potential of GA against different types of cancer and the underlying molecular mechanisms, the other is the bibliometric analysis of GA in cancer and tumor research. The results indicated that lung cancer, prostate cancer, stomach cancer, and colon adenocarcinoma may become a hot topic in further research. Overall, this review provides evidence that GA represents a promising novel, potent, and safe anti-cancer drug candidate for treating cancer.
    Keywords:  application; bibliometric; cancer; gallic acid; tumor
    DOI:  https://doi.org/10.1007/s11655-021-3345-2
  37. Mol Cancer. 2021 Nov 06. 20(1): 143
    Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer.
    Gongmin Zhu, Lijiao Pei, Hongwei Xia, Qiulin Tang, Feng Bi.
      Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.
    Keywords:  Colorectal cancer; Combination therapy; G12C; KRAS; Prognosis; Targeted therapy
    DOI:  https://doi.org/10.1186/s12943-021-01441-4
  38. Anticancer Agents Med Chem. 2021 Nov 07.
    Regulation of cell death mechanisms by melatonin: implications to cancer therapy.
    Zicheng Wang, Yanqing Liu, Ahmed Eleojo Musa.
      Cancer therapy is based on the killing of cancer cells using various therapeutic agents such as radiation, chemotherapy or targeted therapy drugs and immunotherapy. Cancer cells may undergo apoptosis, mitotic catastrophe, necrosis, autophagy, mitophagy, senescence etc., depending on the therapeutic modality and nature of cancer cells. Mutations in some critical genes such as p53 and phosphatase and tensin homolog (PTEN) tumor suppressor genes are associated with immune escaping cancer cells and progression towards tumor progression. Furthermore, the overexpression of some genes such as phosphatidylinositol-3-kinase (PI3K), nuclear factor of Kappa B (NF-κB), cyclooxygenase-2 (COX-2) and mammalian target of rapamycin (mTOR) is associated with resistance of cancer cells to various types of cell death. Melatonin is known as a circadian regulator hormone that has several anti-cancer properties. It has ability to activate tumor suppressor genes and attenuate the expression of survival genes in cancer cells. Modulation of cell death or survival genes that have been disrupted or overexpressed in cancer cells can improve cancer therapy. In this review, we explain the potentials of melatonin in regulating various mechanisms of cancer cell death.
    Keywords:  Apoptosis; Autophagy; Cancer; Melatonin; Mitotic Catastrophe; Senescence
    DOI:  https://doi.org/10.2174/1871520621999211108090712
  39. Neurotherapeutics. 2021 Nov 12.
    Metabolic Transporters in the Peripheral Nerve-What, Where, and Why?
    Atul Rawat, Brett M Morrison.
      Cellular metabolism is critical not only for cell survival, but also for cell fate, function, and intercellular communication. There are several different metabolic transporters expressed in the peripheral nervous system, and they each play important roles in maintaining cellular energy. The major source of energy in the peripheral nervous system is glucose, and glucose transporters 1 and 3 are expressed and allow blood glucose to be imported and utilized by peripheral nerves. There is also increasing evidence that other sources of energy, particularly monocarboxylates such as lactate that are transported primarily by monocarboxylate transporters 1 and 2 in peripheral nerves, can be efficiently utilized by peripheral nerves. Finally, emerging evidence supports an important role for connexins and possibly pannexins in the supply and regulation of metabolic energy. In this review, we will first define these critical metabolic transporter subtypes and then examine their localization in the peripheral nervous system. We will subsequently discuss the evidence, which comes both from experiments in animal models and observations from human diseases, supporting critical roles played by these metabolic transporters in the peripheral nervous system. Despite progress made in understanding the function of these transporters, many questions and some discrepancies remain, and these will also be addressed throughout this review. Peripheral nerve metabolism is fundamentally important and renewed interest in these pathways should help to answer many of these questions and potentially provide new treatments for neurologic diseases that are partly, or completely, caused by disruption of metabolism.
    Keywords:  Connexin; Dorsal root ganglia (DRG); Glucose transporters (GLUT); Metabolism; Monocarboxylate transporters (MCT); Motor neurons; Pannexin; Peripheral nervous system (PNS); Schwann cells (SC); Sensory neurons
    DOI:  https://doi.org/10.1007/s13311-021-01150-2
  40. Biochem Biophys Res Commun. 2021 Nov 02. pii: S0006-291X(21)01500-X. [Epub ahead of print]584 7-14
    A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer.
    Jin Lee, Xiaoxi Chen, Yuming Wang, Tatsunori Nishimura, Mengjiao Li, Satoko Ishikawa, Takiko Daikoku, Junya Kawai, Arinobu Tojo, Noriko Gotoh.
      Patients with triple-negative breast cancer have a poor prognosis as only a few efficient targeted therapies are available. Cancer cells are characterized by their unregulated proliferation and require large amounts of nucleotides to replicate their DNA. One-carbon metabolism contributes to purine and pyrimidine nucleotide synthesis by supplying one carbon atom. Although mitochondrial one-carbon metabolism has recently been focused on as an important target for cancer treatment, few specific inhibitors have been reported. In this study, we aimed to examine the effects of DS18561882 (DS18), a novel, orally active, specific inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism. Treatment with DS18 led to a marked reduction in cancer-cell proliferation; however, it did not induce cell death. Combinatorial treatment with DS18 and inhibitors of checkpoint kinase 1 (Chk1), an activator of the S phase checkpoint pathway, efficiently induced apoptotic cell death in breast cancer cells and suppressed tumorigenesis in a triple-negative breast cancer patient-derived xenograft model. Mechanistically, MTHFD2 inhibition led to cell cycle arrest and slowed nucleotide synthesis. This finding suggests that DNA replication stress occurs due to nucleotide shortage and that the S-phase checkpoint pathway is activated, leading to cell-cycle arrest. Combinatorial treatment with both inhibitors released cell-cycle arrest, but induced accumulation of DNA double-strand breaks, leading to apoptotic cell death. Collectively, a combination of MTHFD2 and Chk1 inhibitors would be a rational treatment option for patients with triple-negative breast cancer.
    Keywords:  Chk1 inhibitor; Folate metabolism; MTHFD2; One carbon metabolism; S-phase check point; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.bbrc.2021.11.001
  41. Nat Metab. 2021 Nov 11.
    Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment.
    Simon Schwörer, Natalya N Pavlova, Francesco V Cimino, Bryan King, Xin Cai, Gina M Sizemore, Craig B Thompson.
      The aberrant production of collagen by fibroblasts is a hallmark of many solid tumours and can influence cancer progression. How the mesenchymal cells in the tumour microenvironment maintain their production of extracellular matrix proteins as the vascular delivery of glutamine and glucose becomes compromised remains unclear. Here we show that pyruvate carboxylase (PC)-mediated anaplerosis in tumour-associated fibroblasts contributes to tumour fibrosis and growth. Using cultured mesenchymal and cancer cells, as well as mouse allograft models, we provide evidence that extracellular lactate can be utilized by fibroblasts to maintain tricarboxylic acid (TCA) cycle anaplerosis and non-essential amino acid biosynthesis through PC activity. Furthermore, we show that fibroblast PC is required for collagen production in the tumour microenvironment. These results establish TCA cycle anaplerosis as a determinant of extracellular matrix collagen production, and identify PC as a potential target to inhibit tumour desmoplasia.
    DOI:  https://doi.org/10.1038/s42255-021-00480-x
  42. Life Sci. 2021 Nov 08. pii: S0024-3205(21)01107-3. [Epub ahead of print] 120120
    Triangulating the pharmacological properties of thymoquinone in regulating reactive oxygen species, inflammation, and cancer: Therapeutic applications and mechanistic pathways.
    Caroline Yuin Hueii Phua, Zhi Ling Teoh, Bey-Hing Goh, Wei Hsum Yap, Yin-Quan Tang.
      Cancer is a heterogeneous disease with high morbidity and mortality rate involving changes in redox balance and deregulation of redox signalling. For decades, studies have involved developing an effective cancer treatment to combat treatment resistance. As natural products such as thymoquinone have numerous health benefits, studies are also focusing on using them as a viable method for cancer treatment, as they have minimal toxic effects compared with standard cancer treatments. Thymoquinone studies have shown numerous mechanisms of action, such as regulation of reactive species interfering with DNA structure, modulating various potential targets and their signalling pathways as well as immunomodulatory effects in vitro and in vivo. Thymoquinone's anti-cancer effect is mainly due to the induction of apoptotic mechanisms, such as activation of caspases, downregulation of precancerous genes, inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), anti-tumour cell proliferation, ROS regulation, hypoxia and anti-metastasis. Insight into thymoquinone's potential as an alternative treatment for chemoprevention and inflammation can be accomplished via compiling these studies, to provide a better understanding on how and why it works, as well as its interactions with common chemotherapeutic treatments.
    Keywords:  Chemoprevention; Inflammation; Reactive oxygen species; Thymoquinone; cancer
    DOI:  https://doi.org/10.1016/j.lfs.2021.120120
  43. J Control Release. 2021 Oct 29. pii: S0168-3659(21)00582-4. [Epub ahead of print]340 221-242
    RGD engineered dendrimer nanotherapeutic as an emerging targeted approach in cancer therapy.
    Afsana Sheikh, Shadab Md, Prashant Kesharwani.
      A bird's eye view is now demanded in the area of cancer research to suppress the suffering of cancer patient and mediate the lack of treatment related to chemotherapy. Chemotherapy is always preferred over surgery or radiation therapy, but they never met the patient's demand of safe medication. Targeted therapy has now been in research that could hinder the unnecessary effect of drug on normal cells but could affect the tumor cells in much efficient manner. Angiogenesis is process involved in development of new blood vessel that nourishes tumor growth. Integrin receptors are over expressed on cancer cells that play vital role in angiogenesis for growth and metastasis of tumor cell. A delivery of RGD based peptide to integrin targeted site could help in its successful binding and liberation of drug in tumor vasculature. Dendrimers, in addition to its excellent pharmacokinetic properties also helps to carry targeting ligand to site of tumor by successfully conjugating with them. The aim of this review is to bring light upon the role of integrin in cancer progression, interaction of RGD to integrin receptor and more importantly the RGD-dendrimer based targeted therapy for the treatment of various cancers.
    Keywords:  Cancer; Dendrimer; Integrin; Nanotechnology; Peptide; RGD; Targeted therapy
    DOI:  https://doi.org/10.1016/j.jconrel.2021.10.028
  44. Front Immunol. 2021 ;12 748573
    Role of PKM2-Mediated Immunometabolic Reprogramming on Development of Cytokine Storm.
    Zhijun Liu, Yifei Le, Hang Chen, Ji Zhu, Dezhao Lu.
      The cytokine storm is a marker of severity of various diseases and increased mortality. The altered metabolic profile and energy generation of immune cells affects their activation, exacerbating the cytokine storm. Currently, the emerging field of immunometabolism has highlighted the importance of specific metabolic pathways in immune regulation. The glycolytic enzyme pyruvate kinase M2 (PKM2) is a key regulator of immunometabolism and bridges metabolic and inflammatory dysfunction. This enzyme changes its conformation thus walks in different fields including metabolism and inflammation and associates with various transcription factors. This review summarizes the vital role of PKM2 in mediating immunometabolic reprogramming and its role in inducing cytokine storm, with a focus on providing references for further understanding of its pathological functions and for proposing new targets for the treatment of related diseases.
    Keywords:  cytokine storm; immunometabolic reprogramming; inflammatory diseases; proinflammatory cytokines; pyruvate kinase M2
    DOI:  https://doi.org/10.3389/fimmu.2021.748573
  45. Saudi J Biol Sci. 2021 Nov;28(11): 6127-6132
    Pyrroloquinoline quinone alleviates oxidative damage induced by high glucose in HepG2 cells.
    Saad Alkahtani, Saud Alarifi, Abdullah A Alkahtane, Gadah Albasher, Mohammed Al-Zharani, Norah M Alhoshani, Norah S Al-Johani, Nada H Aljarba, Md Saquib Hasnain.
      Hyperglycemia as a common metabolic disorder in diabetes led to oxidative stress, inflammation and other complications. Natural and manufactured antioxidants alleviates the side effects of diabetes. The purpose of current study is to investigate the effect of pyrroloquinoline quinine (PQQ) as an antioxidant on the content of glucose-induced oxidative stress generation in the cells of the human hepatocellular liver carcinoma (HepG2) by inhibiting advanced glycation end products (AGEs) formation. The HepG2 cells were exposed to high dose (50 mM) of glucose (HG) only and with PQQ (HG + PQQ). Treatment with high dose increased AGEs formation, expression of receptor for advanced glycation endproducts (RAGE), reactive oxygen species ROS production, and oxidative stress markers in treated HepG2 cells. Interestingly, PQQ significantly reduced AGEs formation and (RAGE) expression, ROS formation, and inflammation induced by glucose. In conclusion, PQQ has a potentiail role as an antioxidant to reduce the oxidative damage during hyperglycemia by AGEs inhibition.
    Keywords:  Cancer; Glucose; Oxidative stress; Pyrroloquinoline quinone
    DOI:  https://doi.org/10.1016/j.sjbs.2021.06.063
  46. FASEB Bioadv. 2021 Nov;3(11): 944-952
    The nervous system: Orchestra conductor in cancer, regeneration, inflammation and immunity.
    Hubert Hondermarck, Pearl S Huang, John A Wagner.
      Although the role of nerves in stimulating cellular growth and dissemination has long been described in tissue regeneration studies, until recently a similar trophic role of nerves in disease was not well recognized. However, recent studies in oncology have demonstrated that the growth and dissemination of cancers also requires the infiltration of nerves in the tumor microenvironment. Nerves generate various neurosignaling pathways, which orchestrate cancer initiation, progression, and metastases. Similarly, nerves are increasingly implicated for their regulatory functions in immunity and inflammation. This orchestrator role of nerves in cellular and molecular interactions during regeneration, cancer, immunity, and inflammation offers new possibilities for targeting or enhancing neurosignaling in human health and diseases.
    Keywords:  cancer; immunity; inflammation; nerves; nervous system; regeneration
    DOI:  https://doi.org/10.1096/fba.2021-00080
  47. Oncogene. 2021 Nov 06.
    Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1.
    Dong Hoon Shin, Sun Ha Kim, Minyoung Choi, Young-Ki Bae, Chungyong Han, Beom K Choi, Sang Soo Kim, Ji-Youn Han.
      We previously found the SLC3A2-NRG1 (S-N) fusion gene in a lung adenocarcinoma specimen without known driver mutations and validated this in 59 invasive mucinous adenocarcinoma (IMA) samples. Interestingly, KRAS mutation coexisted (62.5%) in 10 out of 16 NRG1 fusions. In this study, we examined the role of mutant KRAS in regulating the S-N fusion protein in KRAS mutant (H358) and wild-type (Calu-3) cells. KRAS mutation-mediated increase in MEK1/2 and ERK1/2 activity enhanced disintegrin and metalloproteinase (ADAM)17 activity, which increased the shedding of NRG1 from the S-N fusion protein. The cleavage of NRG1 also increased the phosphorylation of ERBB2-ERBB3 heterocomplex receptors and their downstream signalling pathways, including PI3K/Akt/mTOR, even under activated KRAS mutation signalling. The concurrence of S-N fusion and KRAS mutation synergistically increased cell proliferation, colony formation, tumour growth, and the cells' resistance to EGFR kinase inhibitors more than KRAS mutation alone. Targeted inhibition of MEK1/2, and ADAM17 significantly induced apoptosis singly and when combined with each mutation singly or with chemotherapy in both the concurrent KRAS mutant and S-N fusion xenograft and lung orthotopic models. Taken together, this is the first study to report that KRAS mutation increased NRG1 cleavage from the S-N fusion protein through ADAM17, thereby enhancing the Ras/Raf/MEK/ERK and ERBB/PI3K/Akt/mTOR pathways. Moreover, the coexistence of KRAS mutant and S-N fusion in lung tumours renders them vulnerable to MEK1/2 and/or ADAM17 inhibitors, at least in part, due to their dependency on the strong positive loop between KRAS mutation and S-N fusion.
    DOI:  https://doi.org/10.1038/s41388-021-02097-6
  48. J Photochem Photobiol B. 2021 Nov 02. pii: S1011-1344(21)00232-3. [Epub ahead of print]225 112353
    Phototoxicity of two positive-charged diaryl porphyrins in multicellular tumor spheroids.
    Marzia B Gariboldi, Emanuela Marras, Ivan Vaghi, Arianna Margheritis, Miryam C Malacarne, Enrico Caruso.
      Photodynamic therapy (PDT) is a clinically approved cancer treatment in which reactive oxygen species are formed only when three harmless components, a photosensitizer (PS), light and molecular oxygen, are present at the same time, leading to cell death. Most of the PSs were tested on monolayer cells, but differences between 2D cells and solid tumors significantly limit the value of in vitro PDT studies, whereas the use of 3D spheroid might be more suitable for drug development and preclinical drug testing for PDT. In a previous work we have shown that two positive-charged diaryl porphyrins (2 and 4) were more potent than the corresponding neutral molecules (1 and 3) on a panel of 2D-cultured cancer cell lines. In the present study the photodynamic effects of these molecules have been evaluated on HCT116 and MCF7 spheroids. Induction of apoptotic and necrotic cell death, and generation of reactive oxygen species (ROS) have been also evaluated, along with accumulation and localization of PSs into spheroids. Our findings indicate that 2 and 4 retained their phototoxic effects also in 3D spheroids; furthermore, they were more potent than 1 and 3 and as potent as Foscan (m-THPC), the most successful PS approved for clinical PDT of cancer, used as reference. Although further aspects of their mechanisms of action need to be addressed, our results strongly suggest a potential in vivo photodynamic application of 2 and 4, considering that spheroids represent a more realistic indicator of in vivo therapeutic efficacy than 2D cell lines.
    Keywords:  3D spheroids; Accumulation and localization; Cell death; PDT; Positive-charged diaryl porphyrins; ROS
    DOI:  https://doi.org/10.1016/j.jphotobiol.2021.112353
  49. Biosci Rep. 2021 Nov 10. pii: BSR20211218. [Epub ahead of print]
    Bioactive Cationic Peptides as Potential Agents for Breast Cancer Treatment.
    Marcela Manrique-Moreno, Gloria A Santa-González, Vanessa Gallego.
      Breast cancer continues to affect millions of women worldwide, and the number of new cases dramatically increases every year. The physiological causes behind the disease are still not fully understood. One in every 100 cases can occur in men, and although the frequency is lower than among women, men tend to have a worse prognosis of the disease. Various therapeutic alternatives to combat the disease are available. These depend on the type and progress of the disease, and include chemotherapy, radiotherapy, surgery, and cancer immunotherapy. However, there are several well-reported side effects of these treatments that have a significant impact on life quality, and patients either relapse or are refractory to treatment. This makes it necessary to develop new therapeutic strategies. One promising initiative are bioactive peptides, which have emerged in recent years as a family of compounds with an enormous number of clinical applications due to their broad spectrum of activity. They are widely distributed in several organisms as part of their immune system. The antitumoral activity of these peptides lies in a nonspecific mechanism of action associated with their interaction with cancer cell membranes, inducing, through several routes, bilayer destabilization and cell death. This review provides an overview of the literature on the evaluation of cationic peptides as potential agents against breast cancer under different study phases. First, physicochemical characteristics such as the primary structure and charge are presented. Secondly, information about dosage, the experimental model used, and the mechanism of action proposed for the peptides are discussed.
    Keywords:  antimicrobial peptides; breast cancers; cationic peptides; drug development; new cancer treatments
    DOI:  https://doi.org/10.1042/BSR20211218
  50. Curr Med Chem. 2021 Nov 07.
    Histone modifications and their role in epigenetics of cancer.
    Sumera Zaib, Nehal Rana, Imtiaz Khan.
      Epigenetic regulations play a crucial role in the expression of various genes that are important in the normal cell function. Any alteration in these epigenetic mechanisms can lead to the modification of histone and DNA resulting in the silencing or enhanced expression of some genes causing various diseases. Acetylation, methylation, ribosylation or phosphorylation of histone proteins modifies its interaction with the DNA, consequently changing the ratio of heterochromatin and euchromatin. Terminal lysine residues of histone proteins serve as potential targets of such epigenetic modifications. The current review focuses on the histone modifications, their contributing factors, role of these modifications on metabolism leading to cancer and methylation of histone in cancer affects the DNA repair mechanisms.
    Keywords:  Cancer; Epigenetics; Euchromatin; Heterochromatin; Phosphorylation; Ribosylation
    DOI:  https://doi.org/10.2174/0929867328666211108105214
  51. ACS Appl Mater Interfaces. 2021 Nov 11.
    Heparin-Coated Photosensitive Metal-Organic Frameworks as Drug Delivery Nanoplatforms of Autophagy Inhibitors for Sensitized Photodynamic Therapy against Breast Cancer.
    Quanwei Sun, Xiaohui Hou, Jinming Yang, Mengmeng Zhang, Ye Yang, Yang Liu, Wei Shen, Dengke Yin.
      Photosensitive nanosized metal-organic frameworks (nanoMOFs) with a tunable structure and high porosity have been developed recently as nanophotosensitizers (nanoPSs) for photodynamic therapy (PDT). However, the effect of photodynamic therapy is greatly limited by the fast blood clearance and poor tumor retention of the ordinary nanoPSs. Besides, autophagy, a prosurvival self-cannibalization pathway mediated by autolysosomes, was elevated by cytotoxic reactive oxygen species (ROS) produced during PDT. Herein, a chloroquine phosphate (CQ)-loaded photosensitive nanoMOF coated by heparin was fabricated for sensitized PDT by increasing the tumor accumulation of nanoPSs and abolishing the self-protective autophagy within cancer cells. After internalization by cancer cells, the encapsulated CQ alkalizes autolysosomes and blocks the postautophagy process, which disarm the vigilant cancer cells irritated by PDT and finally enhance the therapeutic effect. Furthermore, the accompanied antiangiogenesis ability of the heparin coat also helps improve the cancer therapy outcomes. This study would open up new horizons for building heparin-coated nanoMOFs and understanding the role of autophagy in cancer therapy.
    Keywords:  autophagy inhibition; breast cancer; heparin; metal−organic framework; sensitized photodynamic therapy
    DOI:  https://doi.org/10.1021/acsami.1c18055
  52. Nat Commun. 2021 Nov 10. 12(1): 6479
    Evolutionary metabolic landscape from preneoplasia to invasive lung adenocarcinoma.
    Meng Nie, Ke Yao, Xinsheng Zhu, Na Chen, Nan Xiao, Yi Wang, Bo Peng, LiAng Yao, Peng Li, Peng Zhang, Zeping Hu.
      Metabolic reprogramming evolves during cancer initiation and progression. However, thorough understanding of metabolic evolution from preneoplasia to lung adenocarcinoma (LUAD) is still limited. Here, we perform large-scale targeted metabolomics on resected lesions and plasma obtained from invasive LUAD and its precursors, and decipher the metabolic trajectories from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC), revealing that perturbed metabolic pathways emerge early in premalignant lesions. Furthermore, three panels of plasma metabolites are identified as non-invasive predictive biomarkers to distinguish IAC and its precursors with benign diseases. Strikingly, metabolomics clustering defines three metabolic subtypes of IAC patients with distinct clinical characteristics. We identify correlation between aberrant bile acid metabolism in subtype III with poor clinical features and demonstrate dysregulated bile acid metabolism promotes migration of LUAD, which could be exploited as potential targetable vulnerability and for stratifying patients. Collectively, the comprehensive landscape of the metabolic evolution along the development of LUAD will improve early detection and provide impactful therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-021-26685-y
  53. Int J Mol Sci. 2021 Oct 21. pii: 11354. [Epub ahead of print]22(21):
    Progress of Phototherapy Applications in the Treatment of Bone Cancer.
    Jiachen Sun, Fei Xing, Joy Braun, Frank Traub, Pol Maria Rommens, Zhou Xiang, Ulrike Ritz.
      Bone cancer including primary bone cancer and metastatic bone cancer, remains a challenge claiming millions of lives and affecting the life quality of survivors. Conventional treatments of bone cancer include wide surgical resection, radiotherapy, and chemotherapy. However, some bone cancer cells may remain or recur in the local area after resection, some are highly resistant to chemotherapy, and some are insensitive to radiotherapy. Phototherapy (PT) including photodynamic therapy (PDT) and photothermal therapy (PTT), is a clinically approved, minimally invasive, and highly selective treatment, and has been widely reported for cancer therapy. Under the irradiation of light of a specific wavelength, the photosensitizer (PS) in PDT can cause the increase of intracellular ROS and the photothermal agent (PTA) in PTT can induce photothermal conversion, leading to the tumoricidal effects. In this review, the progress of PT applications in the treatment of bone cancer has been outlined and summarized, and some envisioned challenges and future perspectives have been mentioned. This review provides the current state of the art regarding PDT and PTT in bone cancer and inspiration for future studies on PT.
    Keywords:  bone cancer; nanoparticles; photodynamic therapy; phototherapy; photothermal therapy; tumor therapy
    DOI:  https://doi.org/10.3390/ijms222111354
  54. Drug Deliv. 2021 Dec;28(1): 2361-2372
    ROS-Activated homodimeric podophyllotoxin nanomedicine with self-accelerating drug release for efficient cancer eradication.
    Bingfeng Liang, Dangxia Zhou.
      Although podophyllotoxin (POD) demonstrates high efficiency to inhibit various cancers, its clinic application is limited to poor bioavailability. Nanoparticles derived from homodimeric prodrugs with high drug loading potential are emerging as promising nanomedicines. However, complete intracellular drug release remains a major hindrance to the use of homodimeric prodrugs-based nanomedicine. We sought to develop a reactive oxygen species (ROS) responsive POD dimeric prodrug by incorporating vitamin K3 (VK3) and Pluronic F127 to synthesize a spheroid nanoparticle (PTV-NPs). PTV-NPs with high POD content could release drugs under the ROS enrichment microenvironment in cancer cells. The released VK3 could produce abundant ROS selectively in tumor cells catalyzed by the overexpressed NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme. In turn, the resultant high ROS concentration promoted the conversion of POD dimeric prodrug to POD monomer, thereby achieving the selective killing of cancer cells with weak system toxicity. In vitro and in vivo studies consistently confirmed that PTV-NPs exhibit high drug loading potential and upstanding bioavailability. They are also effectively internalized by tumor cells, induce abundant intracellular ROS generation, and have high tumor-specific cytotoxicity. This ROS-responsive dimeric prodrug nanoplatform characterized by selective self-amplification drug release may hold promise in the field of antitumor drug delivery.
    Keywords:  Dimeric prodrug; ROS generation; high drug loading; tumor-specific drug release; vitamin K3
    DOI:  https://doi.org/10.1080/10717544.2021.1995076
  55. Cancer Sci. 2021 Nov 09.
    Current Status of Photodynamic Technology for Urothelial Cancer.
    Keiji Inoue, Hideo Fukuhara, Shinkuro Yamamoto, Takashi Karashima, Atsushi Kurabayashi, Mutsuo Furihata, Kazuhiro Hanazaki, Hung Wei Lai, Shun-Ichiro Ogura.
      5-Aminolevulinic acid is a new-generation photosensitizer with high tumor specificity. It has been used successfully in the diagnosis, treatment, and screening of urological cancers including bladder cancer; specifically, it has been used in photodynamic diagnosis to detect tumors by illuminating the lesion with a specific wavelength of light to produce fluorescence in the lesion after administration of 5-aminolevulinic acid, in photodynamic therapy, which induces tumor cell death via production of cytotoxic reactive oxygen species, and in photodynamic screening, in which porphyrin excretion in the blood and urine is used as a tumor biomarker after administration of 5-aminolevulinic acid. In addition to these applications in urological cancers, 5-aminolevulinic acid-based photodynamic technology is expected to be used as a novel strategy for a large number of cancer types because it is based on a property of cancer cells known as the Warburg effect, which is a basic biological property that is common across all cancers.
    DOI:  https://doi.org/10.1111/cas.15193
  56. Int J Mol Sci. 2021 Oct 27. pii: 11630. [Epub ahead of print]22(21):
    Cysteine Restriction in Murine L929 Fibroblasts as an Alternative Strategy to Methionine Restriction in Cancer Therapy.
    Werner Schmitz, Elena Ries, Corinna Koderer, Maximilian Friedrich Völter, Anna Chiara Wünsch, Mohamed El-Mesery, Kyra Frackmann, Alexander Christian Kübler, Christian Linz, Axel Seher.
      Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since the elimination of a single amino acid in the diet is difficult. However, the in vivo turnover rate of cysteine is usually higher than the rate of intake through food. For this reason, every cell can enzymatically synthesize cysteine from methionine, which enables the use of specific enzymatic inhibitors. In this work, we analysed the potential of cysteine restriction (CysR) in the murine cell line L929. This study determined metabolic fingerprints using mass spectrometry (LC/MS). The profiles were compared with profiles created in an earlier work under MetR. The study was supplemented by proliferation studies using D-amino acid analogues and inhibitors of intracellular cysteine synthesis. CysR showed a proliferation inhibition potential comparable to that of MetR. However, the metabolic footprints differed significantly and showed that CysR does not induce classic LEM at the metabolic level. Nevertheless, CysR offers great potential as an alternative for decisive interventions in general and tumour metabolism at the metabolic level.
    Keywords:  LC/MS; amino acid analogues; caloric restriction; cancer therapy; cysteine restriction; cysteine synthase inhibitor; homocysteine; mass spectrometry; methionine restriction
    DOI:  https://doi.org/10.3390/ijms222111630
  57. Nanotechnology. 2021 Nov 10.
    Nanofibrous drug delivery systems for breast cancer: a review.
    Tanveer Hussain, Seeram Ramakrishna, Sharjeel Abid.
      Breast cancer is the most common type of cancer among women. Breast-conserving surgery (BCS) is becoming a preferred approach for treating non-invasive or early-stage breast cancer cases. However, local-regional recurrence (LRR) is one of the critical risk factors after BCS. As many as 10-20% of BCS cases may show LRR within 5 years and almost 50% within 10 years. Radiation therapy is one of the treatments used to prevent LRR after breast-conserving surgery. However, because of possible side-effects of radiation therapy, targeted drug delivery systems based on nanofibers loaded with anti-cancer drugs have been explored in recent years to control LRR after BCS. This paper aims to review different polymers and anti-cancer drugs used for developing nanofibrous drug delivery systems against other breast cancer cell lines. It was observed that the utilization of nanofibers scaffolds after mastectomy could decrease the recurrence of breast cancer cells to a great extent as these nanofibrous scaffolds release drugs in a sustained manner for a prolonged time. Besides, the side effects of chemotherapy on healthy cells could be avoided. To the best of our knowledge, no such review paper is available in the literature that focuses only on the nanofibers-based system for breast cancer therapy.
    Keywords:  Breast Cancer; Drug Delivery; Nanofibers; Nanomedicine
    DOI:  https://doi.org/10.1088/1361-6528/ac385c
  58. Free Radic Biol Med. 2021 Nov 06. pii: S0891-5849(21)00793-0. [Epub ahead of print]177 360-369
    Dissecting in vivo and in vitro redox responses using chemogenetics.
    Markus Waldeck-Weiermair, Shambhu Yadav, Fotios Spyropoulos, Christina Krüger, Arvind K Pandey, Thomas Michel.
      Hydrogen peroxide (H2O2) is the most abundant reactive oxygen species (ROS) within mammalian cells. At low concentrations, H2O2 serves as a versatile cell signaling molecule that mediates vital physiological functions. Yet at higher concentrations, H2O2 can be a toxic molecule by promoting pathological oxidative stress in cells and tissues. Within normal cells, H2O2 is differentially distributed in a variety of subcellular locales. Moreover, many redox-active enzymes and their substrates are themselves differentially distributed within cells. Numerous reports have described the biological and biochemical consequences of adding exogenous H2O2 to cultured cells and tissues, but many of these observations are difficult to interpret: the effects of exogenous H2O2 do not necessarily replicate the cellular responses to endogenous H2O2. In recent years, chemogenetic approaches have been developed to dynamically regulate the abundance of H2O2 in specific subcellular locales. Chemogenetic approaches have been applied in multiple experimental systems, ranging from in vitro studies on the intracellular transport and metabolism of H2O2, all the way to in vivo studies that generate oxidative stress in specific organs in living animals. These chemogenetic approaches have exploited a yeast-derived d-amino acid oxidase (DAAO) that synthesizes H2O2 only in the presence of its d-amino acid substrate. DAAO can be targeted to various subcellular locales, and can be dynamically activated by the addition or withdrawal of its d-amino acid substrate. In addition, recent advances in the development of highly sensitive genetically encoded H2O2 biosensors are providing a better understanding of both physiological and pathological oxidative pathways. This review highlights several applications of DAAO as a chemogenetic tool across a wide range of biological systems, from analyses of subcellular H2O2 metabolism in cells to the development of new disease models caused by oxidative stress in vivo.
    Keywords:  D-amino acid Oxidase; Hydrogen peroxide; Oxidative stress; ROS signaling
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.11.006
  59. Aging (Albany NY). 2021 Nov 12. 13(undefined):
    Low-protein diet applied as part of combination therapy or stand-alone normalizes lifespan and tumor proliferation in a model of intestinal cancer.
    Alina Proske, Judith Bossen, Jakob von Frieling, Thomas Roeder.
      Tumors of the intestinal tract are among the most common tumor diseases in humans, but, like many other tumor entities, show an unsatisfactory prognosis with a need for effective therapies. To test whether nutritional interventions and a combination with a targeted therapy can effectively cure these cancers, we used the fruit fly Drosophila as a model. In this system, we induced tumors by EGFR overexpression in intestinal stem cells. Limiting the amount of protein in the diet restored life span to that of control animals. In combination with a specific EGFR inhibitor, all major tumor-associated phenotypes could be rescued. This form of treatment was also successful in a real treatment scenario, which means when they started after the full tumor phenotype was expressed. In conclusion, reduced protein administration can be a very promising form of adjuvant cancer therapy.
    Keywords:  Drosophila; EGFR; afatinib; cancer; dietary protein restriction; stem cells
    DOI:  https://doi.org/10.18632/aging.203692
  60. Int J Mol Sci. 2021 Oct 28. pii: 11669. [Epub ahead of print]22(21):
    Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies.
    Mahshid Deldar Abad Paskeh, Shafagh Asadi, Amirhossein Zabolian, Hossein Saleki, Mohammad Amin Khoshbakht, Sina Sabet, Mohamad Javad Naghdi, Mehrdad Hashemi, Kiavash Hushmandi, Milad Ashrafizadeh, Sepideh Mirzaei, Ali Zarrabi, Gautam Sethi.
      As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance to therapy. Furthermore, the presence of CSCs leads to cancer recurrence and therefore their complete eradication can have immense therapeutic benefits. The present review focuses on targeting CSCs by natural products in cancer therapy. The growth and colony formation capacities of CSCs have been reported can be attenuated by the dietary agents. These compounds can induce apoptosis in CSCs and reduce tumor migration and invasion via EMT inhibition. A variety of molecular pathways including STAT3, Wnt/β-catenin, Sonic Hedgehog, Gli1 and NF-κB undergo down-regulation by dietary agents in suppressing CSC features. Upon exposure to natural agents, a significant decrease occurs in levels of CSC markers including CD44, CD133, ALDH1, Oct4 and Nanog to impair cancer stemness. Furthermore, CSC suppression by dietary agents can enhance sensitivity of tumors to chemotherapy and radiotherapy. In addition to in vitro studies, as well as experiments on the different preclinical models have shown capacity of natural products in suppressing cancer stemness. Furthermore, use of nanostructures for improving therapeutic impact of dietary agents is recommended to rapidly translate preclinical findings for clinical use.
    Keywords:  cancer stem cells; cancer treatment; drug resistance; medicinal herbs; metastasis; proliferation
    DOI:  https://doi.org/10.3390/ijms222111669
  61. World J Diabetes. 2021 Oct 15. 12(10): 1622-1654
    Estrogens and the regulation of glucose metabolism.
    Marià Alemany.
      The main estrogens: estradiol, estrone, and their acyl-esters have been studied essentially related to their classical estrogenic and pharmacologic functions. However, their main effect in the body is probably the sustained control of core energy metabolism. Estrogen nuclear and membrane receptors show an extraordinary flexibility in the modulation of metabolic responses, and largely explain gender and age differences in energy metabolism: part of these mechanisms is already sufficiently known to justify both. With regard to energy, the estrogen molecular species act essentially through four key functions: (1) Facilitation of insulin secretion and control of glucose availability; (2) Modulation of energy partition, favoring the use of lipid as the main energy substrate when more available than carbohydrates; (3) Functional protection through antioxidant mechanisms; and (4) Central effects (largely through neural modulation) on whole body energy management. Analyzing the different actions of estrone, estradiol and their acyl esters, a tentative classification based on structure/effects has been postulated. Either separately or as a group, estrogens provide a comprehensive explanation that not all their quite diverse actions are related solely to specific molecules. As a group, they constitute a powerful synergic action complex. In consequence, estrogens may be considered wardens of energy homeostasis.
    Keywords:  Antioxidants; Energy metabolism; Estrogen receptors; Estrogens; Glucose; Insulin; Metabolic syndrome
    DOI:  https://doi.org/10.4239/wjd.v12.i10.1622
  62. Cancers (Basel). 2021 Nov 02. pii: 5509. [Epub ahead of print]13(21):
    Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC.
    Inês Godet, Mahelet Mamo, Andrea Thurnheer, D Marc Rosen, Daniele M Gilkes.
      Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this work, we utilize a hypoxia fate-mapping system to determine whether triple-negative breast cancer (TNBC) cells that experience hypoxia in the primary tumor are resistant to chemotherapy at sites of metastasis. Using two orthotopic mouse models of TNBC, we demonstrate that cells that experience intratumoral hypoxia and metastasize to the lung and liver have decreased sensitivity to doxorubicin and paclitaxel but not cisplatin or 5-FU. Resistance to therapy leads to metastatic recurrence caused by post-hypoxic cells. We further determined that the post-hypoxic cells that metastasize are enriched in pathways related to cancer stem cell gene expression. Overall, our results show that even when hypoxic cancer cells are reoxygenated in the bloodstream they retain a hypoxia-induced cancer stem cell-like phenotype that persists and promotes resistance and eventually recurrence.
    Keywords:  breast cancer metastasis; intratumoral hypoxia; recurrence
    DOI:  https://doi.org/10.3390/cancers13215509
  63. Alzheimers Dement. 2021 Nov 10.
    Personalized nutrition for dementia prevention.
    Cécilia Samieri, Hussein N Yassine, Debora Melo van Lent, Sophie Lefèvre-Arbogast, Ondine van de Rest, Gene L Bowman, Nikolaos Scarmeas.
      The role of nutrition has been investigated for decades under the assumption of one-size-fits-all. Yet there is heterogeneity in metabolic and neurobiological responses to diet. Thus a more personalized approach may better fit biological reality and have increased efficacy to prevent dementia. Personalized nutrition builds on the food exposome, defined as the history of diet-related exposures over the lifetime, and on its interactions with the genome and other biological characteristics (eg, metabolism, the microbiome) to shape health. We review current advances of personalized nutrition in dementia research. We discuss key questions, success milestones, and future roadmap from observational epidemiology to clinical studies through basic science. A personalized nutrition approach based on the best prescription for the most appropriate target population in the most relevant time-window has the potential to strengthen dementia-prevention efforts.
    Keywords:  diet; exposome; individualized prevention; nutrition; precision medicine; precision nutrition; prevention; risk factors in epidemiology
    DOI:  https://doi.org/10.1002/alz.12486
  64. Metabolism. 2021 Oct 28. pii: S0026-0495(21)00223-7. [Epub ahead of print]126 154923
    Regulation of NAD+ metabolism in aging and disease.
    Xiaogang Chu, Raghavan Pillai Raju.
      More than a century after discovering NAD+, information is still evolving on the role of this molecule in health and diseases. The biological functions of NAD+ and NAD+ precursors encompass pathways in cellular energetics, inflammation, metabolism, and cell survival. Several metabolic and neurological diseases exhibit reduced tissue NAD+ levels. Significantly reduced levels of NAD+ are also associated with aging, and enhancing NAD+ levels improved healthspan and lifespan in animal models. Recent studies suggest a causal link between senescence, age-associated reduction in tissue NAD+ and enzymatic degradation of NAD+. Furthermore, the discovery of transporters and receptors involved in NAD+ precursor (nicotinic acid, or niacin, nicotinamide, and nicotinamide riboside) metabolism allowed for a better understanding of their role in cellular homeostasis including signaling functions that are independent of their functions in redox reactions. We also review studies that demonstrate that the functional effect of niacin is partially due to the activation of its cell surface receptor, GPR109a. Based on the recent progress in understanding the mechanism and function of NAD+ and NAD+ precursors in cell metabolism, new strategies are evolving to exploit these molecules' pharmacological potential in the maintenance of metabolic balance.
    Keywords:  NAD; Niacin; Niacin receptor; Nicotinamide adenine mononucleotide; Nicotinamide riboside
    DOI:  https://doi.org/10.1016/j.metabol.2021.154923
  65. Int J Mol Sci. 2021 Oct 20. pii: 11315. [Epub ahead of print]22(21):
    Bcl-2 Modulation in p53 Signaling Pathway by Flavonoids: A Potential Strategy towards the Treatment of Cancer.
    Noor Rahman, Haroon Khan, Asad Zia, Asifullah Khan, Sajad Fakhri, Michael Aschner, Karim Gul, Luciano Saso.
      Cancer is a major cause of death, affecting human life in both developed and developing countries. Numerous antitumor agents exist but their toxicity and low efficacy limits their utility. Furthermore, the complex pathophysiological mechanisms of cancer, serious side effects and poor prognosis restrict the administration of available cancer therapies. Thus, developing novel therapeutic agents are required towards a simultaneous targeting of major dysregulated signaling mediators in cancer etiology, while possessing lower side effects. In this line, the plant kingdom is introduced as a rich source of active phytochemicals. The secondary metabolites produced by plants could potentially regulate several dysregulated pathways in cancer. Among the secondary metabolites, flavonoids are hopeful phytochemicals with established biological activities and minimal side effects. Flavonoids inhibit B-cell lymphoma 2 (Bcl-2) via the p53 signaling pathway, which is a significant apoptotic target in many cancer types, hence suppressing a major dysregulated pathway in cancer. To date, there have been no studies reported which extensively highlight the role of flavonoids and especially the different classes of flavonoids in the modulation of Bcl-2 in the P53 signaling pathway. Herein, we discuss the modulation of Bcl-2 in the p53 signaling pathway by different classes of flavonoids and highlight different mechanisms through which this modulation can occur. This study will provide a rationale for the use of flavonoids against different cancers paving a new mechanistic-based approach to cancer therapy.
    Keywords:  Bcl-2; cancer; flavonoids; p53; pharmacology; signaling pathway; therapeutic target
    DOI:  https://doi.org/10.3390/ijms222111315
  66. Cancers (Basel). 2021 Nov 04. pii: 5533. [Epub ahead of print]13(21):
    Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment.
    Samy Ajarrag, Yves St-Pierre.
      Traditional wisdom suggests that galectins play pivotal roles at different steps in cancer progression. Galectins are particularly well known for their ability to increase the invasiveness of cancer cells and their resistance to drug-induced cell death. They also contribute to the development of local and systemic immunosuppression, allowing cancer cells to escape the host's immunological defense. This is particularly true in glioma, the most common primary intracranial tumor. Abnormally high production of extracellular galectins in glioma contributes to the establishment of a strong immunosuppressive environment that favors immune escape and tumor progression. Considering the recent development and success of immunotherapy in halting cancer progression, it is logical to foresee that galectin-specific drugs may help to improve the success rate of immunotherapy for glioma. This provides a new perspective to target galectins, whose intracellular roles in cancer progression have already been investigated thoroughly. In this review, we discuss the mechanisms of action of galectins at different steps of glioma progression and the potential of galectin-specific drugs for the treatment of glioma.
    Keywords:  blood–brain barrier; brain tumors; galectin; glioblastoma; immunotherapy
    DOI:  https://doi.org/10.3390/cancers13215533
  67. J Colloid Interface Sci. 2021 Oct 16. pii: S0021-9797(21)01748-3. [Epub ahead of print]608(Pt 2): 1882-1893
    Stimuli-responsive charge-reversal MOF@polymer hybrid nanocomposites for enhanced co-delivery of chemotherapeutics towards combination therapy of multidrug-resistant cancer.
    Liefeng Hu, Chuxiao Xiong, Gaohui Wei, Yunhao Yu, Sihui Li, Xiaoxing Xiong, Jun-Jie Zou, Jian Tian.
      Combination chemotherapy is a promising strategy for cancer treatment in clinics especially when multidrug-resistant cancer is emerging. One significant challenge remains in achieving sufficient multi-drug delivery into tumor cells to maximize the synergetic therapeutic effect, as it is hard to concentrate drugs in drug-resistant cancer. Therefore herein, metal-organic framework (MOF)-based polymer-coated hybrid nanoparticles (NPs) were devised and constructed for the co-delivery of doxorubicin and cisplatin to enhance combination therapy of multidrug-resistant cancer. The MOF@polymer nanocarrier combined the merits of high multi-drug loading capacity, physiological stability, and tumor microenvironment pH-responsiveness, facilitating simultaneous delivery of drugs into cancer cells and making the most of synergistic antitumor effect. Remarkably, this hybrid nanocarrier maintains a negative surface charge during circulation to guarantee a stable and prolonged process in vivo, and then exposes inner positive MOF after degradation of the outer polymer in the acidic tumor microenvironment to promote multi-drug release, cellular internalization, nuclear localization, and tumor penetration. In vitro and in vivo studies with drug-resistant MCF-7/ADR cancer suggested that the nanocarrier could achieve increased accumulation of drugs in solid tumors, remarkable tumor elimination results as well as minimized side effects, indicating an improved efficacy and safety of combination chemotherapy. MOF@polymer hybrid nanocarriers provide new insights into the development of stimuli-responsive co-delivery systems of multiple drugs.
    Keywords:  Charge reversal; Combination chemotherapy; Hybrid nanoparticles; Metal–organic framework; Multidrug-resistant cancer; Stimuli-responsiveness
    DOI:  https://doi.org/10.1016/j.jcis.2021.10.070
  68. Life Sci. 2021 Oct 29. pii: S0024-3205(21)01097-3. [Epub ahead of print]287 120110
    Role of purinergic system and vitamin D in the anti-cancer immune response.
    Ayodeji A Olabiyi, Daniela F Passos, Jean Lucas G da Silva, Maria R C Schetinger, Daniela B Rosa Leal.
      For several years, scientists have recognized that vitamin D plays an important role in mineral and bone homeostasis. It was mostly used to treat osteoporosis and rickets in the past decades. Vitamin D has also been discovered to be modulator of the immune system and may play a role in a variety of diseases, including autoimmune diseases, in recent years. Vitamin D interaction with the vitamin D receptor (VDR), which has transcriptional imparts and is displayed on a variety of cell types, including those of the immune system, appears to be accountable for the immune-modulating effects. The action of tumor cells and vitamin D were the first to be investigated, but the spotlight is now on immunologic and purinergic systems. We conducted a systematic search in Pub Med as well as Google scholar for studies written in English. Vitamin D, cancer, purinergic signaling, and immune response were among the search words. Vitamin D has the potential to be a useful coadjuvant in cancer therapy and the purinergic system may be a potential treatment target to cancer therapy, according to our findings.
    Keywords:  Cancer; Immune system; Purinergic; VDR; Vitamin D
    DOI:  https://doi.org/10.1016/j.lfs.2021.120110
  69. Molecules. 2021 Oct 22. pii: 6389. [Epub ahead of print]26(21):
    Green Synthesis of Gold Nanoparticles Using Plant Extracts as Beneficial Prospect for Cancer Theranostics.
    Kaushik Kumar Bharadwaj, Bijuli Rabha, Siddhartha Pati, Tanmay Sarkar, Bhabesh Kumar Choudhury, Arpita Barman, Dorothy Bhattacharjya, Ankit Srivastava, Debabrat Baishya, Hisham Atan Edinur, Zulhisyam Abdul Kari, Noor Haslina Mohd Noor.
      Gold nanoparticles (AuNPs) have been widely explored and are well-known for their medical applications. Chemical and physical synthesis methods are a way to make AuNPs. In any case, the hunt for other more ecologically friendly and cost-effective large-scale technologies, such as environmentally friendly biological processes known as green synthesis, has been gaining interest by worldwide researchers. The international focus on green nanotechnology research has resulted in various nanomaterials being used in environmentally and physiologically acceptable applications. Several advantages over conventional physical and chemical synthesis (simple, one-step approach to synthesize, cost-effectiveness, energy efficiency, and biocompatibility) have drawn scientists' attention to exploring the green synthesis of AuNPs by exploiting plants' secondary metabolites. Biogenic approaches, mainly the plant-based synthesis of metal nanoparticles, have been chosen as the ideal strategy due to their environmental and in vivo safety, as well as their ease of synthesis. In this review, we reviewed the use of green synthesized AuNPs in the treatment of cancer by utilizing phytochemicals found in plant extracts. This article reviews plant-based methods for producing AuNPs, characterization methods of synthesized AuNPs, and discusses their physiochemical properties. This study also discusses recent breakthroughs and achievements in using green synthesized AuNPs in cancer treatment and different mechanisms of action, such as reactive oxygen species (ROS), mediated mitochondrial dysfunction and caspase activation, leading to apoptosis, etc., for their anticancer and cytotoxic effects. Understanding the mechanisms underlying AuNPs therapeutic efficacy will aid in developing personalized medicines and treatments for cancer as a potential cancer therapeutic strategy.
    Keywords:  AuNPs; anticancer; gold nanoparticles; green synthesis; plants; therapy
    DOI:  https://doi.org/10.3390/molecules26216389
  70. J Am Coll Nutr. 2021 Nov 10. 1-19
    Tree Turmeric: A Super Food and Contemporary Nutraceutical of 21st Century - A Laconic Review.
    Jasleen Bhasin, Baneet Thakur, Satish Kumar, Vikas Chopra.
      Since ancient times the medicinal plants have been under use as food and potential therapeutic agent for the management of overall health and the use of all plant parts including fruits, seeds, is well reported in the literature. One such plant is Berberis aristata which is rich in vitamins, minerals, and various phytochemicals amongst which Berberine is the principal bioactive compound with a range of reported health benefits, and some of the commercial formulations like Rasaut, Darvyadi Leha are being used for the treatments of jaundice, malaria, typhoid fever, inflammation, eye infection, diarrhea, wound healing, etc. The hepatoprotective, antidiabetic, antitumor, anti-cancerous, properties are the recent additions to its functional importance. Berberine has significant bioactivities in the treatments of different diseases. Besides its remarkable applications, the berberine has low efficacy due to its low solubility in water, poor absorption, and low bioavailability. This problem can be solved by using some techniques like Nanotechnology which has been found to increase its solubility in water, bioavailability, and absorption and hence provide a better delivery system of berberine. This review illuminates the therapeutic applications of the plant Berberis aristata, scientific validation to its traditional uses, role of berberine in the treatment of various diseases through its different bioactivities, major flaws in berberine treatment, and the role of nanotechnology in minimizing those flaws and increasing its overall efficacy. Key teaching pointsPlant Berberis aristata has been used since ancient times for the treatment of various ailments like jaundice, hepatitis, fever, bleeding, inflammation, diarrhea, malaria, skin and eye infections, chronic rheumatism, and urinary disorders.Berberine is the major and most significant phytochemical among numerous phytochemicals present in plant Berberis aristata.Berberine has significantly shown many potent effect against emerging diseases like cancer and diabetes. Besides that, it has also shown antioxidant, anti-inflamation, antimicrobial, hepatoprotective, and anti-gastrointestinal disorder properties.Berberine can be very effective in overcoming the demerits of berberine treatment like poor aqueous solubility, low bioavailability, and poor absorption in the human body in the treatment of various diseases.
    Keywords:   Berberis aristata ; Berberine phytochemicals; bioactive compound; bioavailability
    DOI:  https://doi.org/10.1080/07315724.2021.1958104
  71. Evid Based Complement Alternat Med. 2021 ;2021 2373865
    Mufangji Decoction and Its Active Ingredient Patchouli Alcohol Inhibit Tumor Growth through Regulating Akt/mTOR-Mediated Autophagy in Nonsmall-Cell Lung Cancer.
    Liu Yang, Hongyu Chen, Ruixiao Li, Haoze Li, Xing Rui, Lihong Zhou, Ningning Liu, Qing Ji, Qi Li.
       Background: Nonsmall-cell lung cancer (NSCLC) is the main type of lung cancer, whose morbidity and mortality rank first among malignant tumors. More than 70% of NSCLC patients are diagnosed at locally advanced or advanced stage, missing the best operation period. Chemotherapy and targeted therapy are important means for the treatment of advanced NSCLC, but various side effects seriously affect the curative effect and the life quality of NSCLC patients. Our previous clinical practice has shown that Mufangji Decoction, a classic traditional Chinese medicine, has a significant curative effect in the treatment of NSCLC, but the specific mechanism is not clear. This study intends to explore the potential mechanism of Mufangji Decoction and its active ingredient patchouli alcohol against NSCLC and to provide a scientific basis for the prevention and treatment of NSCLC by traditional Chinese medicine.
    Methods: The in vivo and in vitro experiments were performed to evaluate the antitumor effects and investigate the underlying mechanism of Mufangji Decoction and its active ingredient patchouli alcohol. Network pharmacology was applied to analyze the effective ingredients and potential targets or signaling pathways of Mufangji Decoction.
    Results: Our current study shows that Mufangji Decoction can effectively inhibit the growth of subcutaneous transplantation of NSCLC. The following network pharmacological analysis and in vivo experiment suggest that patchouli alcohol is one of the main active ingredients of Mufangji Decoction and exerts antitumor effects. Further mechanism investigation reveals that the antitumor effect of patchouli alcohol is related to the induction of Akt/mTOR signaling pathway-mediated autophagy in NSCLC cells.
    Conclusion: Mufangji Decoction and its active ingredient patchouli alcohol might exert their antitumor effects in NSCLC partly through regulating Akt/mTOR-mediated autophagy, providing the evidence that traditional Chinese medicine might be a key approach for NSCLC treatment via targeting the Akt/mTOR signal axis.
    DOI:  https://doi.org/10.1155/2021/2373865
  72. Int J Mol Sci. 2021 Oct 25. pii: 11500. [Epub ahead of print]22(21):
    Delphinidin and Its Glycosides' War on Cancer: Preclinical Perspectives.
    Anshul Sharma, Hyo-Kyoung Choi, Yeon-Kye Kim, Hae-Jeung Lee.
      Until now, several studies have looked at the issue of anthocyanin and cancer, namely the preventive and inhibitory effects of anthocyanins, as well as the underlying molecular processes. However, no targeted review is available regarding the anticarcinogenic effects of delphinidin and its glycosides on various cancers and their plausible molecular mechanisms. Considerable evidence shows significant anticancer properties of delphinidin-rich preparations and delphinidin alone both in vitro and in vivo. This review covers the in vitro and preclinical implications of delphinidin-mediated cell protection and cancer prevention; thus, we strongly recommend that delphinidin-rich preparations be further investigated as potential functional food, dietary antioxidant supplements, and natural health products targeting specific chronic diseases, including cancer. In addition to in vitro investigations, future research should focus on more animal and human studies to determine the true potential of delphinidin.
    Keywords:  anthocyanidins; anthocyanins; cancer; delphinidin; metastasis; proliferation
    DOI:  https://doi.org/10.3390/ijms222111500
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