title: Old drug, new trick: repurposing metformin for gynecologic cancers?
abstract: OBJECTIVE
  There is increasing pre-clinical and clinical evidence that metformin, a commonly used diabetes medication, has a protective effect in cancer. The aim of this review is to discuss metformin's anti-cancer molecular mechanisms of action and to summarize the current literature demonstrating metformin's potential in gynecologic cancer prevention and treatment.
  
  
  METHODS
  A PubMed search was conducted combining the keywords "metformin" with "neoplasm", "uterine neoplasms", "ovarian neoplasms", and "uterine cervical neoplasms". Studies published in English between 1994 and 2014 were included.
  
  
  RESULTS
  Pre-clinical studies in endometrial, ovarian, and cervical cancer suggest that metformin inhibits the growth of cancer cells. The primary molecular mechanism mediating this effect appears to be the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of mammalian targets of rapamycin (mTOR). The pre-clinical findings are augmented by clinical studies indicating that metformin use is associated with a reduced risk of cancer and improved survival in diabetic women with ovarian and endometrial cancers. No clinical analyses have evaluated metformin use and cervical cancer. Overall, the data showing a favorable effect of metformin is strongest for endometrial and ovarian cancer and prospective clinical testing is ongoing in these two malignancies.
  
  
  CONCLUSIONS
  Numerous clinical studies have reported an association between metformin use by diabetic patients and improved outcomes in gynecologic cancers. In addition, pre-clinical reports have identified plausible biological mechanisms to explain the molecular mechanism of action of metformin in cancer. However, the most important question remains unanswered: Will metformin be effective against cancer in patients without diabetes? Until this question is answered with prospective clinical testing, the role of metformin in the treatment or prevention of gynecologic malignancies remains theoretical and the clinical use of metformin as a cancer therapeutic is experimental.
authors.affiliation: Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA.
authors.forename: Terri
authors.initials: T
authors.lastname: Febbraro
authors.affiliation: Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.affiliation: Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA. Electronic address: iromero@uchicago.edu.
authors.forename: Iris L
authors.initials: IL
authors.lastname: Romero
mesh_terms: D005260:Female; D005833:Genital Neoplasms, Female / Q000517:prevention & control*; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*
chemical_list: D008687:Metformin
keywords: Endometrial cancer; Glucose; Gynecologic cancer; Metformin; Ovarian cancer