A potential role for the antidiabetic drug metformin in the treatment of platinum resistant ovarian cancer

Objective: The treatment of ovarian cancer is complicated by high drug resistance often linked to over-expression of focal adhesion kinase (FAK). Additionally, cancer cells preferentially metabolize glucose and hyperglycaemia is considered a promotor of tumour growth. In this context, the anti-diabetic drug metformin is now being investigated as a potential treatment. The present study assessed the cytotoxic effects of metformin and FAK inhibitor, PF-573228, as therapeutic adjuncts with carboplatin in the treatment of platinum resistant OVCAR3 ovarian cancer cells. Method: OVCAR-3 cells were maintained in eagle's minimum essential medium (EMEM) complete media (80% EMEM; 20% FBS; 1% antibiotic) with a culture environment of 5% CO2 at 37 °C. Cells were exposed to metformin (5 mM, 25 mM, 50 mM), carboplatin (1 μM, 10 μM, 100 μM) and FAK inhibitor, PF-573228 (5 μM, 50 μM, 100 μM) over 24 hours in triplicates to determine IC50. Twenty-four-hour combination treatments of metformin plus carboplatin, metformin plus PF-573228 and metformin plus carboplatin plus PF-573228 were carried out in triplicates. Cytotoxicity tests were performed using the MTT assay and absorbance was measured by a spectrophotometer at 570 nm. Results: Metformin, carboplatin and FAK inhibitor (PF-573228), alone induced a dose-dependent cytotoxicity in OVCAR-3 cells with IC50 of 26.31 mM, 57 μM and 100 μM, respectively. For combination treatments, metformin significantly enhanced the cytotoxic effects of carboplatin by 10% (p = 0.0002) and PF-573228 by 36% (p < 0.00001). The combination result of all three revealed 94% (p < 0.000001) cytotoxicity which was significantly higher than metformin only (29% p < 0.05) or carboplatin and PF573228 only which produced 50% cytotoxicity. Conclusion: Metformin potentiates the cytotoxic effects of carboplatin and PF-573228, in platinum resistant ovarian cancer cells.