Abstract 504: Metformin potently inhibits cell proliferation, adhesion and invasion in ovarian cancer cells

Abstract

Abstract ABSTRACT Objectives: Metformin is an anti-diabetic drug that has been shown to have anti-tumorgenic effects by behaving as a novel mTOR inhibitor. Metformin has been shown to suppress cancer cell growth, but little is known of its potential to halt metastatic spread. Thus, our goal was to assess the effect of metformin on proliferation, adhesion and invasion in ovarian cancer cell lines. Methods: Four ovarian cancer cell lines, SKOV3, CAOV3, OVCAR3 and IGROV1 were used. Cell proliferation was assessed by MTT assay after exposure to metformin. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by Annexin V-FITC assay. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the expression of the downstream targets of metformin, including AMPK and the ribosomal protein S6. Inhibition of adhesion and invasion by metformin was assessed by in vitro adhesion assay and ChemoTx® invasion assay. Results: Metformin potently inhibited growth in a dose-dependent manner in all four ovarian cancer cell lines (IC50 of 0.1-1 mM) (p=0.00001-0.0121). Treatment with metformin resulted in G1 arrest, induction of apoptosis and decreased hTERT expression. Western immunoblot analysis demonstrated that metformin induced phosphorylation of AMPK, its immediate downstream mediator, and decreased phosphorylation of the S6 protein, a key target of the mTOR pathway, within 24 hours of exposure. Metformin inhibited cellular adhesion in the ovarian cancer cell lines by 10-23% at 1 mM (p=0.04-0.00001) and 25-35% at 10 mM (p=0.05-0.00001). In addition, metformin decreased invasion by 7-21% at 1 mM (p=0.03-0.0009) and 29-42% at 10 mM (p=0.03-0.0012). Conclusions: We report that metformin is a potent inhibitor of cell proliferation and exhibits anti-metastatic effects in ovarian cancer cells. Thus, metformin may have potential as a targeted chemotherapeutic agent in the treatment of ovarian cancer. More work is needed to determine if metformin will be universally beneficial in all ovarian cancer patients versus selectively efficacious in a subset of ovarian cancer patients, such as those women who are obese and/or diabetic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 504. doi:1538-7445.AM2012-504