New Perspective for an Old Antidiabetic Drug: Metformin as Anticancer Agent

Abstract

Metformin, an inexpensive, well-tolerated oral agent that is commonly used in the first-line treatment for type 2 diabetes, has become the focus of intense research as a potential anticancer agent. This research reflects a convergence of epidemiologic, clinical, and preclinical evidence, suggesting that metformin may lower cancer risk in diabetics and improve outcomes of many common cancers. Notably, metformin mediates an approximately 30 % reduction in the lifetime risk of cancer in diabetic patients. There is growing recognition that metformin may act (1) directly on cancer cells, primarily by impacting mitochondrial respiration leading to the activation of the AMP-activated protein kinase (AMPK), which controls energy homeostasis in cells, but also through other mechanisms or (2) indirectly on the host metabolism, largely through AMPK-mediated reduction in hepatic gluconeogenesis, leading to reduced circulating insulin levels and decreased insulin/IGF-1 receptor-mediated activation of the PI3K pathway. Support for this comes from the observation that metformin inhibits cancer cell growth in vitro and delays the onset of tobacco carcinogen-induced lung cancer in mice and that metformin and its analog phenformin delay spontaneous tumor development cancer-prone transgenic mice. The potential for both direct antitumor effects and indirect host-mediated effects has sparked enormous interest, but has led to added challenges in translating preclinical findings to the clinical setting. Nonetheless, the accumulation of evidence has been sufficient to justify initiation of clinical trials of metformin as an anticancer agent in the clinical setting, including a large-scale adjuvant study in breast cancer, with additional studies planned.

Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytesin vitrovia mTOR-signaling pathway

“…Recent clinical and experimental studies have revealed that metformin treatment can reduce cancer risk and improve the prognosis of cancer patients (Leone et al, 2014). Clinical studies have shown that psoriasis patients on metformin have a better treatment response than those not on metformin (Brauchli et al, 2008).…”

Evaluation of Effects of Metformin in Primary Ovarian Cancer Cells

“…Further it can reduce the risks of endometrial carcinoma and inhibit endometrial carcinoma cells growth involving PI3K/Akt pathway (Goodwin et al, 2008;Pollak., 2010;Xie et al, 2011;Emami et al, 2013;. Moreover, researchers think that metformin prevents lung cancer caused by smoking by reducing IGF-1 and insulin levels by suppressing mTOR which is a protein that promotes the growth of lung cancer cells (Leone et al, 2014). Further detailed analyses and clinical trials will be necessary to identify the specific molecular mechanisms, and to determine whether metformin would have similar effects in vivo.…”

Effect of Ondansetron on Metformin Pharmacokinetics and Response in Healthy Subjects

“…The drug is also taken by women with gestational diabetes who may experience nausea and vomiting (Siu et al, 2002). Moreover, increased understanding of the molecular mechanisms of metformin action has led to clinical trials of the drug for the prevention and treatment of various cancers (Beck and Scheen, 2013;Malek et al, 2013;Leone et al, 2014). Therefore, it is clinically possible that a 5-HT 3 antagonist and metformin may be prescribed to a patient together.…”