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Nature Cancer Nov 2022The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and...
The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.
Topics: Animals; Mice; Humans; Pancreatic Neoplasms; Asparagine; Adenocarcinoma; Symbiosis; Tumor Microenvironment
PubMed: 36411320
DOI: 10.1038/s43018-022-00463-1 -
Trends in Cancer Aug 2021Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its... (Review)
Review
Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its toxicity. Findings from retrospective epidemiological studies in diabetic populations and preclinical laboratory models have demonstrated that biguanides possess antitumor activities that suggest their repurposing for cancer prevention and treatment. However, a better understanding of how these biguanides behave as antitumor agents is needed to guide their improved applications in cancer therapy, spurring increased interest in their pharmacology. Here, we present evidence for proposed mechanisms of action related to their antitumor activity, including their effects on central carbon metabolism in cancer cells and immune-modulating activity, and then review progress on biguanide repurposing in cancer therapeutics and the possible re-evaluation of phenformin as a cancer therapeutic agent.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biguanides; Cell Line, Tumor; Clinical Trials as Topic; Disease Models, Animal; Drug Repositioning; Drug Synergism; Humans; Immune Checkpoint Inhibitors; Neoplasms; Oxidative Phosphorylation; Protein Kinase Inhibitors; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 33865798
DOI: 10.1016/j.trecan.2021.03.001 -
The Journal of Investigative Dermatology Jan 2021The results in the article by Zhou et al. (2020) demonstrate that the antidiabetic drug phenformin inhibits skin tumor growth and promotes keratinocyte differentiation,...
The results in the article by Zhou et al. (2020) demonstrate that the antidiabetic drug phenformin inhibits skin tumor growth and promotes keratinocyte differentiation, and an underlying mechanism is also defined. In this commentary, additional potential mechanisms through which phenformin may exert its antitumorigenic effect are described. Thus, the proposed repurposing of phenformin to treat skin cancer has merit.
Topics: Adenosine Monophosphate; Drug Repositioning; Humans; Hypoglycemic Agents; Neoplasms; Phenformin
PubMed: 33342506
DOI: 10.1016/j.jid.2020.06.008 -
Biomedicine & Pharmacotherapy =... Mar 2022Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain... (Review)
Review
Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain malignancies with poor prognosis. Therefore, the development of innovative management strategies for refractory cancers and brain tumors is important. In states of mitochondrial dysfunction - commonly encountered in malignant cells - cells mostly shift to anaerobic glycolysis by increasing the expression of LDHA (Lactate Dehydrogenase-A) gene. Oxamate, an isosteric form of pyruvate, blocks LDHA activity by competing with pyruvate. By blocking LDHA, it inhibits protumorigenic cascades and also induces ROS (reactive oxygen species)-induced mitochondrial apoptosis of cancer cells. In preclinical studies, oxamate blocked the growth of invasive pituitary adenomas, medulloblastomas and glioblastomas. Oxamate also increases temozolomide and radiotherapy sensitivity of glioblastomas. Oxamate is highly polar, which may preclude its clinical utilization due to low penetrance through cell membranes. However, this obstacle could be overcome with nanoliposomes. Moreover, different oxamate analogs were developed which inhibit LDHC4, an enzyme also involved in cancer progression and germ cell physiology. Lastly, phenformin, an antidiabetic agent, exerts anticancer effects via complex I inhibition in the mitochondria and leading the overproduction of ROS. Oxamate combination with phenformin reduces the lactic acidosis-causing side effect of phenformin while inducing synergistic anticancer efficacy. In sum, oxamate as a single agent and more efficiently with phenformin has high potential to slow the progression of aggressive cancers with special emphasis to brain tumors.
Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Glycolysis; Humans; L-Lactate Dehydrogenase; Mitochondria; Neoplasms; Oxamic Acid; Phenformin; Radiation Tolerance; Reactive Oxygen Species; Temozolomide
PubMed: 35124385
DOI: 10.1016/j.biopha.2022.112686 -
Redox Biology Jul 2019Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of... (Review)
Review
Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a mechanism of drug resistance in a range of oncogene-addicted cancers. However, the development of inhibitors against STAT3 has been fraught with challenges such as poor delivery or lack of specificity. Clinical experience with small molecule STAT3 inhibitors has seen efficacy signals, but this success has been tempered by drug limiting toxicities from off-target adverse events. It has emerged in recent years that, contrary to the Warburg theory, certain tumor types undergo metabolic reprogramming towards oxidative phosphorylation (OXPHOS) to satisfy their energy production. In particular, certain drug-resistant oncogene-addicted tumors have been found to rely on OXPHOS as a mechanism of survival. Multiple cellular signaling pathways converge on STAT3, hence the localization of STAT3 to the mitochondria may provide the link between oncogene-induced signaling pathways and cancer cell metabolism. In this article, we review the role of STAT3 and OXPHOS as targets of novel therapeutic strategies aimed at restoring drug sensitivity in treatment-resistant oncogene-addicted tumor types. Apart from drugs which have been re-purposed as OXPHOS inhibitors for-anti-cancer therapy (e.g., metformin and phenformin), several novel compounds in the drug-development pipeline have demonstrated promising pre-clinical and clinical activity. However, the clinical development of OXPHOS inhibitors remains in its infancy. The further identification of compounds with acceptable toxicity profiles, alongside the discovery of robust companion biomarkers of OXPHOS inhibition, would represent tangible early steps in transforming the therapeutic landscape of cancer cell metabolism.
Topics: Animals; Drug Resistance, Neoplasm; Humans; Mitochondria; Neoplasms; Oncogenes; Oxidative Phosphorylation; STAT3 Transcription Factor
PubMed: 30594485
DOI: 10.1016/j.redox.2018.101073 -
Proceedings of the National Academy of... Mar 2022SignificanceMetformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose...
SignificanceMetformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose concentrations has remained elusive. Most studies to date have attributed metformin's glucose-lowering effects to inhibition of complex I activity. Contrary to this hypothesis, we show that inhibition of complex I activity in vitro and in vivo does not reduce plasma glucose concentrations or inhibit hepatic gluconeogenesis. We go on to show that metformin, and the related guanides/biguanides, phenformin and galegine, inhibit complex IV activity at clinically relevant concentrations, which, in turn, results in inhibition of glycerol-3-phosphate dehydrogenase activity, increased cytosolic redox, and selective inhibition of glycerol-derived hepatic gluconeogenesis both in vitro and in vivo.
Topics: Animals; Electron Transport Complex IV; Gluconeogenesis; Glucose; Glycerol; Glycerolphosphate Dehydrogenase; Guanidines; Hypoglycemic Agents; Liver; Metformin; Oxidation-Reduction; Phenformin; Pyridines
PubMed: 35238637
DOI: 10.1073/pnas.2122287119 -
Seminars in Nephrology May 2023The good old days were not good, at least in terms of treating patients with type 2 diabetes. In the 1960s, the development of a radioimmunoassay for insulin permitted... (Review)
Review
The good old days were not good, at least in terms of treating patients with type 2 diabetes. In the 1960s, the development of a radioimmunoassay for insulin permitted determination of the distinguishing features of type 1 and type 2 diabetes. The latter was treated with sulfonylureas and then phenformin, although the mechanisms of action at the time were unknown. The University Group Diabetes Program was a randomized controlled trial experienced by my medical generation, and the results were dramatic, both medically and legally. Next came the thiazolidinediones. All compounds were associated with weight gain and any end point benefits were uncertain. Nevertheless, basic science explained how glucose is sensed and even found a home for sulfonylureas in some patients. Next came the boom in renin-angiotensin-aldosterone system blockade, sacred ground for many, albeit the benefits were less than astounding. Other wonder drugs came and went. Over the decades, great strides were made in defining the pathology of diabetic renal disease, which is appropriate because the condition has become a primary cause of end-stage renal failure. Nonetheless, recent advances have turned around a depressing situation and are reasons for optimism. We now have compounds that actually could help patients with type 2 diabetes. One hundred years after insulin's introduction, it is high time.
Topics: Humans; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Renin-Angiotensin System; Kidney Failure, Chronic; Insulins; Randomized Controlled Trials as Topic
PubMed: 37862743
DOI: 10.1016/j.semnephrol.2023.151426 -
Cancer Science Sep 2019Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously...
Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5-fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor-β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X-linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2-mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor-β/Smad signaling.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemoradiotherapy; Colon; Colonic Neoplasms; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Fluorouracil; Humans; Male; Metformin; Mice; Mice, Nude; Neoplasm Recurrence, Local; Phenformin; Rectal Neoplasms; STAT3 Transcription Factor; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Xenograft Model Antitumor Assays
PubMed: 31278880
DOI: 10.1111/cas.14124 -
International Journal of Molecular... Jul 2019Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as... (Review)
Review
Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug.
Topics: Animals; Antineoplastic Agents; Diabetes Mellitus, Type 2; Humans; Models, Biological; Neoplasms; Phenformin; Risk Factors
PubMed: 31284513
DOI: 10.3390/ijms20133316