Repurposing old drugs to chemoprevention: the case of metformin
Introduction
There is intense interest in the cancer prevention research community regarding the potential of metformin, the front-line oral treatment for type II diabetes (T2D), to prevent a wide variety of cancers. The increased risk of cancer in hyper-insulinemic states such as metabolic syndrome or T2D is well recognized [1]. Meta-analyses have estimated relative risks (RR) of 1.1-2.5 for cancer at various organ sites in patients with T2D [2]. These sites include liver, breast, bladder, endometrium, pancreas, colorectum, and kidney, as well as non-Hodgkin lymphomas, among others. Metformin (1,1-dimethylbiguanide) is a cheap generic drug with a well understood safety profile and track record of tolerability that has been shown to decrease the progression from prediabetes to overt diabetes [3]. Numerous epidemiologic studies and meta-analyses have documented an association between metformin use and reduced cancer incidence and mortality (fully discussed below), making metformin an ideal candidate for drug re-purposing. However, recent recognition of time-related biases as a major potential source of error in some epidemiologic studies calls for a re-evaluation of the literature linking metformin use to reduced cancer incidence [4], [5]. Here, we examine the current state of understanding of the potential of metformin use to reduce cancer incidence and mortality, from putative mechanisms of action through the limited data on current and ongoing clinical trials.
Section snippets
Molecular mechanisms of metformin in cancer and diabetes
Despite its long history of clinical use in the diabetes setting, the precise mechanisms underlying the anti-hyperglycemic and anti-hyperinsulinemic effects, as well as the anti-cancer properties, of metformin are still incompletely understood. Two basic routes of metformin action have potential to contribute to its anti-neoplastic activity (Fig. 1) [6], [7]: (1) an indirect route involving “endocrine-type effects” related to its insulin-lowering activity which may slow tumor proliferation in
Animal carcinogenesis studies
The evidence for a cancer preventive effect for metformin, however, has not been consistently demonstrated in vivo in animal studies. Multiple studies examining the effect of metformin on breast tumors occurring spontaneously in outbred mouse strains or in transgenic Her2/neu mice or carcinogen-treated rodents have shown results ranging from no effect to minor, albeit statistically significant, decrease in tumor multiplicity and increase in latency when given early and at high doses [19], [31],
Epidemiologic studies
The epidemiologic literature regarding metformin use and cancer incidence and mortality, both overall and linked to specific organ sites, has exploded over the past decade. Multiple meta-analyses have now reported a decrease in cancer incidence of approximately 14%–40%, along with a decrease in mortality in the same range (Table 1) [45], [46], [47], [48], [49], [50]. Organ sites reported to be thus protected include breast, colon, liver, pancreas, prostate, endometrium, and lung, among others.
Review of clinical trials
Although the literature reviewed above suggests a potential role for metformin in cancer prevention, well-crafted clinical trials addressing specific research questions in uniform cohorts will be needed to eventually determine if metformin is, indeed, effective in reducing cancer incidence. Here we review the status of completed and ongoing clinical trials that address the potential efficacy of metformin to prevent cancer in a variety of clinical settings. Eleven early phase studies of
Conclusions
The emerging data from preclinical, epidemiologic, and clinical studies suggest that there is a signal for cancer preventive potential with metformin use. There is biologic plausibility for a cancer preventive effect given the multiple ways that metformin can interfere with cancer promoting signalling pathways. However, both animal and epidemiologic studies have shown somewhat mixed effects. Further, the epidemiologic literature reviewed above relates only to individuals with diabetes and the
Financial disclosure/Conflicts of interest
The authors do not report any potential financial conflicts.
Funding/support
The study was supported by grants from the Italian Association for Cancer Research AIRC (IG 12072), the Italian Ministry of Health (RF-2009-1532226), and the Italian League Against Cancer (14/08) to Andrea DeCensi. Andrea DeCensi’s work was partially performed during a sabbatical at the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health.
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