Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction

// Zaid Al-Wahab 1 , Ismail Mert 1, 2 , Calvin Tebbe 2 , Jasdeep Chhina 2 , Miriana Hijaz 2 , Robert T. Morris 1 , Rouba Ali-Fehmi 3 , Shailendra Giri 4, 5 , Adnan R. Munkarah 2, 5 , Ramandeep Rattan 2, 5 1 Wayne State University, Detroit, MI, USA 2 Division of Gynecologic Oncology, Department of Women’s Health, Henry Ford Hospital, Detroit, MI, USA 3 Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA 4 Department of Neurology, Henry Ford Hospital, Detroit, MI, USA 5 Josephine Cancer Institute, Henry Ford Hospital, Detroit, MI, USA Correspondence to: Ramandeep Rattan, e-mail: [email protected] Keywords: ovarian cancer, metformin, calorie restriction, AMPK, mTOR(definition) Received: February 05, 2015      Accepted: February 23, 2015      Published: March 26, 2015 ABSTRACT Caloric restriction(definition) (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.