title: Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction.
abstract: Caloric restriction (CR) was recently demonstrated by us to restrict ovarian cancer growth in vivo. CR resulted in activation of energy regulating enzymes adenosine monophosphate activated kinase (AMPK) and sirtuin 1 (SIRT1) followed by downstream inhibition of Akt-mTOR. In the present study, we investigated the effects of metformin on ovarian cancer growth in mice fed a high energy diet (HED) and regular diet (RD) and compared them to those seen with CR in an immunocompetent isogeneic mouse model of ovarian cancer. Mice either on RD or HED diet bearing ovarian tumors were treated with 200 mg/kg metformin in drinking water. Metformin treatment in RD and HED mice resulted in a significant reduction in tumor burden in the peritoneum, liver, kidney, spleen and bowel accompanied by decreased levels of growth factors (IGF-1, insulin and leptin), inflammatory cytokines (MCP-1, IL-6) and VEGF in plasma and ascitic fluid, akin to the CR diet mice. Metformin resulted in activation of AMPK and SIRT1 and inhibition of pAkt and pmTOR, similar to CR. Thus metformin can closely mimic CR's tumor suppressing effects by inducing similar metabolic changes, providing further evidence of its potential not only as a therapeutic drug but also as a preventive agent.
authors.affiliation: Wayne State University, Detroit, MI, USA.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Al-Wahab
authors.affiliation: Wayne State University, Detroit, MI, USA.|Division of Gynecologic Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Ismail
authors.initials: I
authors.lastname: Mert
authors.affiliation: Division of Gynecologic Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Tebbe
authors.affiliation: Division of Gynecologic Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Jasdeep
authors.initials: J
authors.lastname: Chhina
authors.affiliation: Division of Gynecologic Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Miriana
authors.initials: M
authors.lastname: Hijaz
authors.affiliation: Wayne State University, Detroit, MI, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Morris
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Rouba
authors.initials: R
authors.lastname: Ali-Fehmi
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.|Josephine Cancer Institute, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Giri
authors.affiliation: Division of Gynecologic Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.|Josephine Cancer Institute, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Adnan R
authors.initials: AR
authors.lastname: Munkarah
authors.affiliation: Division of Gynecologic Oncology, Department of Women's Health, Henry Ford Hospital, Detroit, MI, USA.|Josephine Cancer Institute, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Rattan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D031204:Caloric Restriction; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects*; D004789:Enzyme Activation; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden
chemical_list: D016588:Anticarcinogenic Agents; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D008687:Metformin; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: AMPK; calorie restriction; mTOR; metformin; ovarian cancer