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

Oncotarget. 2015 May 10;6(13):10908-23. doi: 10.18632/oncotarget.3434.

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.

Keywords: AMPK; calorie restriction; mTOR; metformin; ovarian cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Caloric Restriction*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Energy Metabolism / drug effects*
  • Enzyme Activation
  • Female
  • Inflammation Mediators / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Metformin / pharmacology*
  • Mice, Inbred C57BL
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / prevention & control*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Sirtuin 1 / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Tumor Burden

Substances

  • Anticarcinogenic Agents
  • Inflammation Mediators
  • Intercellular Signaling Peptides and Proteins
  • Metformin
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • AMP-Activated Protein Kinases
  • SIRT1 protein, human
  • Sirtuin 1