Metformin: An anti-diabetic drug to fight cancer

Daugan, Marie V.; Wojcicki, Amélie Dufaÿ; d’Hayer, Benoit; Boudy, Vincent

doi:10.1016/j.phrs.2016.10.006

Cited by 140 publications

(124 citation statements)

References 123 publications

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“…Metformin is known to activate AMPK while inhibit PI3K/AKT24. Our immunoblotting result with U87 cells confirmed this notion and further revealed a potentiation effect of Akti-1/2 on AMPK activation (Fig.…”

Section: Resultssupporting

confidence: 85%

Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells

Zhou

Zhang

et al. 2017

Sci Rep

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AKT serves as an epigenetic modulator that links epigenetic regulation to cell survival and proliferation while the epigenetic mediator OCT4 critically controls stem cell pluripotency and self-renewal. Emerging evidence indicated their complicated interplays in cancer cells and cancer stem cells (CSCs), and inhibiting either one may activate the other. Thus, in this study, we propose a strategy to targeting both factors simultaneously. Firstly, a combination of an OCT4-specific shRNA and the specific AKT inhibitor Akti-1/2 potently suppressed the propagation of human embryonal carcinoma cells, adherent cancer cells and stem-like cancer cells, establishing the proof-of-concept that dual inhibiting OCT4 and AKT can effectively target various cancer cells. Next, we combined Akti-1/2 with metformin, a widely-prescribed drug for treating type 2 diabetes, which was reported to down-regulate OCT4 expression. The metformin + Akti-1/2 combo significantly altered multiple signaling and epigenetic pathways, induced growth arrest and cell death of adherent and stem-like glioblastoma U87 cells, and attenuated their tumorigenicity in vivo. Taken together, we demonstrate here that simultaneously targeting an epigenetic mediator and an epigenetic modulator, by dual inhibiting OCT4 and AKT, can have significantly improved efficacies over single treatment in suppressing the propagation of CSCs as well as the entire bulk of differentiated cancer cells.

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Section: Resultssupporting

confidence: 85%

Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells

Zhou

Zhang

et al. 2017

Sci Rep

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“…Metformin transport into cells involves an active uptake process mediated by organic cation transporter (OCT) 1, 2 or 3 (8). To determine the level of OCT1 expression in thyroid cancer, we analyzed RNA Seq data derived from The Cancer Genome Atlas (TCGA) database incorporating 507 thyroid cancer patients.…”

Section: Resultsmentioning

confidence: 99%

“…OCT1 downregulation limits the antineoplastic effects of metformin, further supporting the significant role of OCT1 expression in cancer response to metformin (28). The same metformin transporter plays a major role in metformin action in the liver (8). …”

Section: Discussionmentioning

confidence: 99%

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Metformin Targets Mitochondrial Glycerophosphate Dehydrogenase to Control Rate of Oxidative Phosphorylation and Growth of Thyroid Cancer In Vitro and In Vivo

Thakur

Daley

Gaskins

et al. 2018

Clinical Cancer Research

118

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Purpose Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) in the liver. There are no data on the expression and role of mGPDH as a metformin target in cancer. In this study, we evaluated mGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental design We analyzed mGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on mGPDH expression were determined by qRT-PCR and western blot. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and mGPDH expression in metastatic thyroid cancer mouse models. Results We show for the first time that mGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that mGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of mGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high mGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth inhibitory effects of metformin in vitro and in vivo. Conclusion Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.

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“…Интересно, что бигуаниды оказывают ингибирующее влияние на некоторые ангиогенные белки и, таким обра-зом, являются антиангиогенными препаратами [7]. Так, недавно было доказано, что метформин снижает уровень экспрессии как эндотелиального фактора роста сосудов, так и тромбоцитарного фактора роста, которые являются ключевыми участниками ангиогенеза [8,9].…”

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