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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Aug 2021Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its...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Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its toxicity.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 -
Cell Jul 2015The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well...
The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well understood why pyruvate supplementation allows cells lacking ETC function to proliferate. We used a CRISPR-based genetic screen to identify genes whose loss sensitizes human cells to phenformin, a complex I inhibitor. The screen yielded GOT1, the cytosolic aspartate aminotransferase, loss of which kills cells upon ETC inhibition. GOT1 normally consumes aspartate to transfer electrons into mitochondria, but, upon ETC inhibition, it reverses to generate aspartate in the cytosol, which partially compensates for the loss of mitochondrial aspartate synthesis. Pyruvate stimulates aspartate synthesis in a GOT1-dependent fashion, which is required for pyruvate to rescue proliferation of cells with ETC dysfunction. Aspartate supplementation or overexpression of an aspartate transporter allows cells without ETC activity to proliferate. Thus, enabling aspartate synthesis is an essential role of the ETC in cell proliferation.
Topics: Aspartate Aminotransferase, Cytoplasmic; Aspartic Acid; Cell Proliferation; DNA, Mitochondrial; Electron Transport; Humans; Jurkat Cells; Mitochondria; Mutation; Phenformin; Pyruvic Acid
PubMed: 26232224
DOI: 10.1016/j.cell.2015.07.016 -
Proceedings of the National Academy of... Mar 2021-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis....
-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. The understanding that both compensatory pathways and intrinsic redundancy in cell systems exists implies that the use of combination therapies for effective and durable responses is necessary. Additionally, the most effective targeted therapies exploit an "Achilles' heel" and are tailored to the genetics of the cancer under study. We performed an unbiased screen on select metabolic targeted therapy combinations and correlated sensitivity with over 20 subsets of cancer. We found that -amplified neuroblastoma is hypersensitive to the combination of an inhibitor of the lactate transporter MCT1, AZD3965, and complex I of the mitochondrion, phenformin. Our data demonstrate that MCT4 is highly correlated with resistance to the combination in the screen and lowly expressed in -amplified neuroblastoma. Low MCT4 combines with high expression of the MCT2 and MCT1 chaperone CD147 in -amplified neuroblastoma, altogether conferring sensitivity to the AZD3965 and phenformin combination. The result is simultaneous disruption of glycolysis and oxidative phosphorylation, resulting in dramatic disruption of adenosine triphosphate (ATP) production, endoplasmic reticulum stress, and cell death. In mouse models of -amplified neuroblastoma, the combination was tolerable at concentrations where it shrank tumors and did not increase white-blood-cell toxicity compared to single drugs. Therefore, we demonstrate that a metabolic combination screen can identify vulnerabilities in subsets of cancer and put forth a metabolic combination therapy tailored for -amplified neuroblastoma that demonstrates efficacy and tolerability in vivo.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Basigin; Cell Line, Tumor; Cell Proliferation; Electron Transport Complex I; Gene Amplification; Humans; Mice; Mitochondria; Monocarboxylic Acid Transporters; N-Myc Proto-Oncogene Protein; Neuroblastoma; Phenformin; Pyrimidinones; Symporters; Thiophenes; Xenograft Model Antitumor Assays
PubMed: 33762304
DOI: 10.1073/pnas.2009620118 -
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 -
Oncotarget Jul 2017Phenformin's recently demonstrated efficacy in melanoma and Gleevec's demonstrated anti-proliferative action in chronic myeloid leukemia may lie within these drugs'... (Review)
Review
Phenformin's recently demonstrated efficacy in melanoma and Gleevec's demonstrated anti-proliferative action in chronic myeloid leukemia may lie within these drugs' significant pharmacokinetics, pharmacodynamics and structural homologies, which are reviewed herein. Gleevec's success in turning a fatal leukemia into a manageable chronic disease has been trumpeted in medical, economic, political and social circles because it is considered the first successful targeted therapy. Investments have been immense in omics analyses and while in some cases they greatly helped the management of patients, in others targeted therapies failed to achieve clinically stable recurrence-free disease course or to substantially extend survival. Nevertheless protein kinase controlling approaches have persisted despite early warnings that the targeted genomics narrative is overblown. Experimental and clinical observations with Phenformin suggest an alternative explanation for Gleevec's mode of action. Using 13C-guided precise flux measurements, a comparative multiple cell line study demonstrated the drug's downstream impact on submolecular fatty acid processing metabolic events that occurred independent of Gleevec's molecular target. Clinical observations that hyperlipidemia and diabetes are both reversed in mice and in patients taking Gleevec support the drugs' primary metabolic targets by biguanides and statins. This is evident by structural data demonstrating that Gleevec shows pyridine- and phenyl-guanidine homology with Phenformin and identical phenylcarbamoyl structural and ligand binding homology with Lipitor. The misunderstood mechanism of action of Gleevec is emblematic of the pervasive flawed reasoning that genomic analysis will lead to targeted, personalized diagnosis and therapy. The alternative perspective for Gleevec's mode of action may turn oncotargets towards metabolic channel reaction architectures in leukemia and melanoma, as well as in other cancers.
Topics: Atorvastatin; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Melanoma; Metformin; Phenformin
PubMed: 28418852
DOI: 10.18632/oncotarget.16238 -
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 -
RSC Chemical Biology Apr 2021Rising bacterial antibiotic resistance is a global threat. To deal with it, new antibacterial agents and antiseptic materials need to be developed. One alternative in... (Review)
Review
Rising bacterial antibiotic resistance is a global threat. To deal with it, new antibacterial agents and antiseptic materials need to be developed. One alternative in this quest is the organometallic derivatization of well-established antibacterial drugs and also the fabrication of advanced metal-based materials having antibacterial properties. Metal-based agents and materials often show new modes of antimicrobial action which enable them to overcome drug resistance in pathogenic bacterial strains. This review summarizes recent (2017-2020) progress in the field of organometallic-derived antibacterial drugs and metal-based materials having antibacterial activity. Specifically, it covers organometallic derivatives of antibacterial drugs including β-lactams, ciprofloxacin, isoniazid, trimethoprim, sulfadoxine, sulfamethoxazole, and ethambutol as well as non-antibacterial drugs like metformin, phenformin and aspirin. Recent advances and reported clinical trials in the use of metal-based nanomaterials as antibiofouling coatings on medical devices, as photocatalytic agents in indoor air pollutant control, and also as photodynamic/photothermal antimicrobial agents are also summarized.
PubMed: 34458790
DOI: 10.1039/d0cb00218f -
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 -
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