Ovarian cancer is most lethal cause of gynecological types of cancer mainly because of acquired drug resistance and poor diagnosisis. In majority of cases it is detected at an advanced stage when it is likely to have spread beyond ovaries. Combination of platinum drugs with paclitaxel is the current mode of treatment. Although cancer cells respond well to the drug combination, relapse often occurs for which drugs fail to function. We have designed a number of novel platinums aimed to overcome platinum resistance in ovarian cancer. We also applied combinations of platinums and tumor active phytochemicals such as curcumin, EGCG, thymoquinone, resveratrol, ursolic acid and genistein to overcom drug resistance. This presentation will provide a brief overview of novel platinums designed in our lab with special emphasis on recent studies on combinations of platinum with phytochemicals and protein expression.
Activity of the compounds alone and in sequenced combination in ovarian cancer cell lines including A2780, A2780cisR and A2780ZD0473R were determined using MTT reduction assay. Drug uptake and drug-DNA binding were determined using developed protocols. Proteomic studies involving 2D gel electrophoresis and mass spectrometry were carried out to characterize key proteins associated with platinum resistance.
Generally but not always sequenced combinations with 2 to 4 h time gap were found to be synergistic. The variation in combined drug action with the change in sequence of administration clearly indicates that the action of one drug has modulated that of the other. Proteomic studies have identified over thirty proteins believed to be associated with platinum resistance in ovarian cancer. They belong to six major groups including cytoskeletal proteins, molecular chaperone and stress related proteins, proteins involved in detoxification and drug resistance, proteins involved in metabolic processes and mRNA processing proteins. The proteins are restored to normalcy due to treatment with synergistic combinations.
If confirmed in vivo, the results of the study indicate that appropriate combinations of targeted therapy and tumor active phytochemicals may providing an effective and affordable means of overcoming drug resistance in ovarian cancer.
Citation Format: Fazlul Huq. Synergism from combination of targeted therapy with tumor active phytochemicals in ovarian tumor models and changes in protein expression. [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 3484. doi:10.1158/1538-7445.AM2015-3484