School of Medical Sciences, Sydney Medical School, University of Sydney, Australia
Background: Acquired drug resistance and poor diagnosis is serves to make ovarian cancer as being the most lethal cause of gynecological types of cancer in women. While cancer cells respond well to the combinations of platinum drugs and paclitaxel, relapse often occurs for which the drugs fail to function. The present study aimed to investigate synergism from combination of platinum drugs and designed platinums with tumour active phytochemicals including curcumin, EGCG, thymoquinone, resveratrol, ursolic acid, 6-shoagol, ellagic acid, mycophenlic acid and genistein in human ovarian tumour models. Methods: 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. Results: Generally but not always sequenced combinations with 2 to 4 h time gap were found to be more 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 close to forty 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. Conclusion: If confirmed in vivo, the results of the study suggest that appropriate combinations of targeted therapy and tumour active phytochemicals may provide an effective and affordable means of overcoming drug resistance in ovarian cancer. Conflict of interest: The author declares no conflict of interest.
Keywords: Ovarian cancer, platinum drugs, phytochemicals.