Background and aims
Resistance to platinum-based chemotherapy remains a major obstacle in the treatment against human ovarian cancer. In this study, binary combinations of platinum compounds: cisplatin, carboplatin and oxaliplatin with phytochemicals: artemisinin, thymoquinone, curcumin, lupeol and oleanolic acid have been applied to human ovarian cancer cell lines: A2780, A2780cisR, and A2780ZD0473R using three different sequences of administration (0/0h, 0/4h and 4/0h) where 0/0h means both the drugs added at the same time, 0/4h means platinum added first followed phytochemical 4 h later and 4/0h means the converse.
Cytotoxicity was determined based on MTT reduction MTT assay. Median effect analysis was done to characterize combined drug action and combination Index (CI) was used as a measure of synergism or antagonism whereas cellular accumulation of platinum, platinum to DNA binding levels and proteomic studies were done to provide insight into drug resistance and synergism from combined drug action.
The combinations of platinum and the phytochemicals produced sequence- and concentration-dependent synergism in the ovarian tumour models. The degree of synergism was greater in the resistant cell lines than the parent cell line. It was found that combination with phytochemicals also increased intracellular accumulation of platinum and the level of platinum binding with DNA. Proteomic study identified a number of proteins believed to be associated with cisplatin resistance in ovarian cancer cells A2780 and A2780cisR. The expression of the proteins were either down- or up-regulated in A2780cisR cell line as compared to A2780 cell line but fully or partially restored after treatment with synergistic combinations.
The results of the study indicate that appropriately sequenced combinations of platinum drugs and phytochemicals can provide a means of overcoming drug resistance in ovarian cancer.
Citation Format: Safiah I. Althurwi, Jun Qing Yu,, Philip Beale, Charles Chan, Fazlul Huq. Sequenced combinations of platinum drugs and phytochemicals towards overcoming drug resistance in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2534. doi:10.1158/1538-7445.AM2015-2534