Metformin as a Novel Component of Metronomic Chemotherapeutic Use: A Hypothesis

The hypoglycemic agent metformin has been found to possess chemopreventive and direct antitumor properties. Several clinical studies worldwide are using it as a monotherapy or as an add-on therapy with chemotherapeutic drugs to determine prospectively its efficacy and safety in treating human cancer. In terms of its mechanism of action, metformin moderately inhibits electron transport in mitochondria to cause increased AMP:ATP ratios, which antagonize gluconeogenesis in hepatocytes, and to promote catabolism in most tissues through activating AMP-activated kinase (AMPK). Inhibition of mammalian target of rapamycin signaling through activation of AMPK has been suggested to mediate the antitumor effects of metformin. However, AMPK-independent growth-inhibitory properties of metformin on tumor cells have also been described, suggesting that antagonizing electron transport per se may be cytostatic or cytotoxic to cancer cells. In addition, metformin was hypothesized to display antiviral and antimalarial effects in 1950s, and recently it has been found to promote the generation of CD8 T memory lymphocytes, suggesting that its immune-activating effects may also contribute to its observed antitumor and chemopreventive properties. Chronic administration of metformin has an acceptable toxicity profile and is well tolerated by millions of patients with type 2 diabetes worldwide, suggesting that this agent could potentially be a therapeutic component with low intensity if given in continuous dosing/frequent usage schedules. These metronomic strategies show that metformin can inhibit tumor angiogenesis and activate antitumor immunity, indicating a potential therapeutic interaction with immune potentiation, antitumor effects, and an acceptable toxicity profile. Here, we review current knowledge on metformin's signaling, metabolic, and immune effects, as well as data from clinical drug trials, to discuss how the interplay may orchestrate the antitumor effects of this agent, particularly in combination with reduced-intensity or metronomic chemotherapeutic use.