title: Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning.
abstract: Metformin exerts antitumor effects mainly through AMP-activated protein kinase [AMPK] activation and phosphatidylinositol 3-kinase [PI3K]-Akt-mammalian target of rapamycin [mTOR] inhibition. This drug leads to activation of the cellular energy-sensing liver kinase B1 [LKB1]/AMPK pathway. LKB1 is implicated as a tumor suppressor gene in molecular pathogenesis of different malignancies. AMPK is a serine/threonine protein kinase that acts as an ultra-sensitive cellular energy sensor maintaining the energy balance within the cell. AMPK activation inhibits mRNA translation and proliferation in cancer cells via down-regulation of PI3K/Akt/mTOR pathway. Moreover, metformin decreases the production of insulin, insulin-like growth factor, inflammatory cytokines and vascular endothelial growth factor, and therefore it exerts anti-mitotic, anti-inflammatory and anti-angiogenetic effects. Recent in vitro and experimental data suggest that metformin electively targets cancer stem cells, and acts together with chemotherapy to block tumor growth in different cancers. Several epidemiological studies and meta-analysis have shown that metformin use is associated with decreased cancer risk and/or reduced cancer mortality for different malignancies. The present review analyzes the recent biological and clinical data suggesting a possible growth-static effect of metformin also in gynecological cancers. The large majority of available clinical data on the anti-cancer potential of metformin are based on observational studies. Therefore long-term phase II-III clinical trials are strongly warranted to further investigate metformin activity in gynecological cancers.
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Gynecology and Obstetrics, University of Pisa, Italy. Electronic address: a.gadducci@med.unipi.it.
authors.forename: Angiolo
authors.initials: A
authors.lastname: Gadducci
authors.affiliation: Division of Gynecology, University of Turin, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Biglia
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Gynecology and Obstetrics, University of Pisa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Tana
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Gynecology and Obstetrics, University of Pisa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Cosio
authors.affiliation: Division of Gynecology, University of Turin, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Gallo
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D058492:Drug Repositioning; D016889:Endometrial Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008687:Metformin / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008687:Metformin
keywords: AMP-activated protein kinase [AMPK]; Breast cancer; Chemoprevention; Diabetes; Endometrial cancer; Insulin; Insulin-like growth factor [IGF]; Mammalian target of rapamycin [mTOR]; Metformin; Ovarian cancer