Repurposing old drugs to chemoprevention: the case of metformin

Abstract

Multiple epidemiologic studies have documented an association between the anti-diabetic agent metformin and reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models or more recent epidemiological studies. The purpose of this paper is to examine metformin's chemopreventive potential by reviewing relevant mechanisms of action, preclinical evidence of efficacy, updated epidemiologic evidence after correction for potential biases and confounders, and recently completed and ongoing clinical trials. Although repurposing drugs with well described mechanisms of action and safety profiles is an appealing strategy for cancer prevention, there is no substitute for well executed late phase clinical trials to define efficacy and populations that are most likely to benefit from an intervention.

Keywords: Chemoprevention; Metformin; Repurposing.

Figure 1

Two basic routes of metformin action have potential to contribute to its anti-neoplastic activity. (1) The indirect route involves “endocrine-type effects” related to its insulin-lowering activity (left arrow from “Metformin” box); this action may slow tumor proliferation in hyperinsulinemic patients. (2) Direct actions in target cells result from metformin's suppression of ATP production due to its inhibition of mitochondrial complex I (right arrow from “Metformin” box). Both routes of metformin activity converge on the mTOR (mammalian target of rapamycin) pathway resulting in inhibition of mTOR's pro-proliferative activity.