Morris, Kadane; Reboe-benjamin Monique; Levy, Arkene S.
Author Affiliation, Ana.
A potential role for the antidiabetic drug metformin in the treatment of platinum resistant ovarian cancer
West Indian Medical Journal
Date of Publication
Objective: The treatment of ovarian cancer is complicated by high drug-resistance often linked to overexpression 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 minimal essential medium (EMEM) complete media (80% EMEM; 20% FBS; 1% antibiotic) with a culture environment of 5% CO2 and 37 蚓. Cells were exposed to Metformin (5 mM, 25 mM, 50 mM), Carboplatin (1 然, 10 然, 100 然) and FAK inhibitor, PF-573228 (5 然, 50 然, 100 然) over 24 hours period in triplicates to determine IC50. Twenty-four hour combination treatments of metformin+carboplatin, metformin+PF-573228 and metformin+carboplatin+PF-573228 were carried out in triplicates. Cytotoxicity tests were performed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (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 然 and 100 然, 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.....