Abstract
BackgroundCombination drug therapy appears a promising approach to overcome drug resistance and reduce drug-related toxicities in ovarian cancer treatments. In this in vitro study, we evaluated the antitumor efficacy of cisplatin in combination with Bithionol (BT) against a panel of ovarian cancer cell lines with special focus on cisplatin-sensitive and cisplatin-resistant cell lines. The primary objectives of this study are to determine the nature of the interactions between BT and cisplatin and to understand the mechanism(s) of action of BT-cisplatin combination.MethodsThe cytotoxic effects of drugs either alone or in combination were evaluated using presto-blue assay. Cellular reactive oxygen species were measured by flow cytometry. Immunoblot analysis was carried out to investigate changes in levels of cleaved PARP, XIAP, bcl-2, bcl-xL, p21 and p27. Luminescent and colorimetric assays were used to test caspases 3/7 and ATX activity.ResultsThe efficacy of the BT-cisplatin combination depends upon the cell type and concentrations of cisplatin and BT. In cisplatin-sensitive cell lines, BT and cisplatin were mostly antagonistic except when used at low concentrations, where synergy was observed. In contrast, in cisplatin-resistant cells, BT-cisplatin combination treatment displayed synergistic effects at most of the drug ratios/concentrations. Our results further revealed that the synergistic interaction was linked to increased reactive oxygen species generation and apoptosis. Enhanced apoptosis was correlated with loss of pro-survival factors (XIAP, bcl-2, bcl-xL), expression of pro-apoptotic markers (caspases 3/7, PARP cleavage) and enhanced cell cycle regulators p21 and p27.ConclusionIn cisplatin-resistant cell lines, BT potentiated cisplatin-induced cytotoxicity at most drug ratios via enhanced ROS generation and modulation of key regulators of apoptosis. Low doses of BT and cisplatin enhanced efficiency of cisplatin treatment in all the ovarian cancer cell lines tested. Our results suggest that novel combinations such as BT and cisplatin might be an attractive therapeutic approach to enhance ovarian cancer chemosensitivity. Combining low doses of cisplatin with subtherapeutic doses of BT can ultimately lead to the development of an innovative combination therapy to reduce/prevent the side effects normally occurring when high doses of cisplatin are administered.
Highlights
Combination drug therapy appears a promising approach to overcome drug resistance and reduce drug-related toxicities in ovarian cancer treatments
BT-cisplatin combination cytotoxicity studies The objective of the present study is to investigate the effects of BT-cisplatin combination in ovarian cancer cell lines with special focus on cisplatin-sensitive and cisplatinresistant isogenic pair of cell lines
BT-cisplatin combination-induced cytotoxicity profiles on individual ovarian cancer cell lines are described below: A2780 and A2780-Cisplatin-resistant variants of IGROV-1 and A2780 (CDDP) isogenic pair A2780 When A2780 cells were pretreated with BT followed by cisplatin addition, there was synergy only at lower BT (3.25 and 6.25 μM) and cisplatin (1.56–6.25 μM) concentrations (Fig. 1a)
Summary
Combination drug therapy appears a promising approach to overcome drug resistance and reduce drug-related toxicities in ovarian cancer treatments. Subsequent treatment with second-line or third-line agents (after interim non-platinum therapy) results in less than 33% response rate due to the increase of resistance to these drugs [6,7,8,9]. Platinum-based chemotherapy is still an effective treatment for ovarian cancer in spite of severe side effects and development of resistance associated with its use [10]. In order to mitigate the side effects and resistance resulting from cisplatin-based chemotherapy, it is essential to investigate new drugs which are non-toxic and work in alternative/similar pathways to cisplatin, providing additional therapeutic options in ovarian cancer
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