Repurposing metformin for the prevention of cancer and cancer recurrence

Heckman-Stoddard, Brandy M.; DeCensi, Andrea; Sahasrabuddhe, Vikrant V.; Ford, Leslie G.

doi:10.1007/s00125-017-4372-6

Cited by 244 publications

(192 citation statements)

References 63 publications

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“…The antidiabetic drug metformin is known to alter cellular metabolism through mitochondrial OXPHOS complex I inhibition [76] [77] [78] [79] [80]. Researchers have attempted to harness this anti-metabolic effect to treat a variety of cancers [81]. In a pilot study by Curry et al , patients with squamous cell carcinoma of the head and neck were treated with metformin during the time between their initial diagnostic biopsy and surgical resection.…”

Section: Discussionmentioning

confidence: 99%

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

Wilde

Roche

Domingo‐Vidal

et al. 2017

Seminars in Oncology

261

213

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Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation (OXPHOS). Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize OXPHOS. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and is highly expressed in cancer-associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers.

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Section: Discussionmentioning

confidence: 99%

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

Wilde

Roche

Domingo‐Vidal

et al. 2017

Seminars in Oncology

261

213

View full text Add to dashboard Cite

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“…In fact, SFN reduces hepatic glucose production and improves glucose control in patients with T2DM (Axelsson et al, 2017). Interestingly, some evidence suggests that metformin may be effective in preventing other nonglycemic pathophenotypes of the NRF2 diseasome, including cardiovascular (Nesti and Natali, 2017), respiratory (Sato et al, 2016), digestive (Bauer and Duca, 2016), neurodegenerative (Markowicz-Piasecka et al, 2017), autoimmune (Schuiveling et al, 2017), and neoplastic (Heckman-Stoddard et al, 2017) disorders. The mechanism of action of metformin is not completely clear, but it involves inhibition of mitochondrial complex I, thus increasing the AMP/ATP ratio (El-Mir et al, 2000;Owen et al, 2000) and leading to activation of the energy sensor AMPK (Hardie, 2004;Rena et al, 2017).…”

Section: E Repurposing Instead Of De Novo Drug Discovery and Developmentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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“…12 Possible inhibitory mechanisms of metformin have also prompted epidemiological studies as well as prospective clinical trials (reviewed in Ref. 1,13,14).…”

Section: Introductionmentioning

confidence: 99%

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis

Seliger

Genbrugge

Gorlia

et al. 2019

Intl Journal of Cancer

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Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression‐free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65–1.16; HR for PFS = 0.84; 95% CI = 0.64–1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68–1.38; HR for PFS = 1.02; 95% CI = 0.74–1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42–1.10; HR for PFS = 0.57; 95% CI = 0.36–0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51–1.56; HR for PFS = 1.05; 95% CI = 0.64–1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities.

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Repurposing metformin for the prevention of cancer and cancer recurrence

Cited by 244 publications

References 63 publications

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis

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