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A Potential Role for the Antidiabetic Drug Metformin in the Treatment of Platinum Resistant Ovarian Cancer

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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 promoter of tumour growth. In this context, the anti-diabetic drug metformin is 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) [3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide] assay and absorbance was measured by a spectrophotometer at 570 nm.
Results: Metformin, carboplatin and FAK inhibitor (PF-573228), alone induced a dosedependent 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. 
08 Sep, 2015
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e-Published: 12 Feb, 2016
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