Repurposing metformin for cancer treatment: current clinical studies

Young Kwang Chae, Ayush Arya, Mary-Kate Malecek, Daniel Sanghoon Shin, Benedito Carneiro, Sunandana Chandra, Jason Kaplan, Aparna Kalyan, Jessica K Altman, Leonidas Platanias, Francis Giles, Young Kwang Chae, Ayush Arya, Mary-Kate Malecek, Daniel Sanghoon Shin, Benedito Carneiro, Sunandana Chandra, Jason Kaplan, Aparna Kalyan, Jessica K Altman, Leonidas Platanias, Francis Giles

Abstract

In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment.

Keywords: cancer; clinical trials; metformin.

Conflict of interest statement

There is no conflict of interest.

Figures

Figure 1. Possible mechanisms of anti-cancer activity…
Figure 1. Possible mechanisms of anti-cancer activity of metformin
The inhibition of mTORC1 is mediated by reducing the downstream effects of IGF-1 and insulin hormone receptor binding, increased TSC2 phosphorylation by AMPK, Rag GTPase mediated inhibition and phosphorylation of mTOR binding raptor by AMPK. This leads to inhibition of mRNA translation, ribosomal biogenesis and cell growth. Metformin also potentiates the immune system by reducing immune exhaustion of CD 8+ tumor infiltrating lymphocytes through phenotypic switching to memory cells, thus enhancing the immune response to cancer cells. Abbreviations: AMP, Adenosine monophosphate; AMPK, AMP activated protein kinase; GTPase, Ras-related GTPase; mTORC1, Mammalian receptor of rapamycin; TSC2, Tuberous sclerosis complex protein 2; PI3K, Phosphoinositide 3 kinase; Akt, Protein kinase B; IL-2, Interleukin-2; TNFα, Tumor necrosis factor -α; IFNγ, Interferon γ

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