Old Drug, New Trick

Abstract

In recent years, it is becoming increasingly clear that cancer cells have metabolic derangements that may make them vulnerable to drugs that disrupt metabolism. One such agent with great potential for treatment of gynecologic oncology is metformin, an oral biguanide currently used in patients with diabetes and polycystic ovarian syndrome. An observational study published in 2005 first suggested that metformin has a protective effect in cancer. The data showed that patients with type 2 diabetes taking metformin had a lower risk of dying of cancer than did patients who did not use metformin. Subsequently, several other observational studies and 2 meta-analyses suggested an association between metformin use and reduced cancer risk and/or improved cancer survival. The first report indicating that metformin was cytotoxic to ovarian cancer cells and inhibited their growth in vitro was published in 2008; this finding has now been supported by several other studies. Preclinical reports have suggested plausible biological mechanisms for the anticancer actions of metformin. The aim of this review was to examine metformin’s anticancer mechanisms of action and to summarize preclinical and epidemiological evidence demonstrating metformin’s potential in gynecologic cancer prevention and treatment. A MEDLINE (PubMed) search was conducted to identify articles published between 1994 and 2014 combining the MESH keywords “metformin” with “neoplasm,” “uterine neoplasms,” “ovarian neoplasms,” and “uterine cervical neoplasms.” Studies investigating the mechanism of action of metformin in ovarian cancer have focused on activation of AMPK (AMP-activated protein kinase) and the subsequent inhibition of downstream mTOR (mammalian targets of rapamycin). It has also been suggested that metformin selectively targets ovarian cancer stem cells. A number of clinical studies have reported that metformin reduces the risk of gynecologic cancers in diabetic women and improves survival; the strongest data showing a favorable anticancer effect of metformin were for endometrial and ovarian cancer. In contrast to these 2 cancers, clinical analyses have not evaluated metformin in cervical cancer. Accumulating evidence from numerous clinical studies has reported an association between use of metformin by diabetic patients and improved outcomes in endometrial and ovarian cancer. Currently, prospective clinical studies are evaluating this agent in patients with these 2 malignancies. However, it has not been demonstrated that metformin can improve survival from gynecologic cancers in patients without diabetes. Until prospective clinical trials are performed, the role of metformin in the treatment or prevention of gynecologic malignancies is unclear, and the clinical use of metformin for cancer is experimental.