Synergism from combination of targeted therapy and phytochemicals in colorectal cancer

Abstract

Colorectal cancer is the second most common cancer in women and third in men, accounting for 9.7 % of all cancers incidence. Oxaliplatin is a platinum-based anticancer drug used typically in combination with folinic acid and 5-fluorouracil for treatment against colorectal cancer. However, numerous side effects such as nausea and vomiting, GI toxicity, anaemia, immunodeficiency, ototoxicity, nephrotoxicity, and neurotoxicity are associated with its use. These can be decreased by lowering dose of oxaliplatin. Phytochemicals that can act as antioxidants have been used by people in treatment against cancer throughout human history because of their low toxicity and the ease in availability. Besides providing protection against cancer, they can also kill cancer cells. Studies show that chemopreventive agents would boost activity of anticancer drugs and thus improve treatment outcome. In this study, resveratrol, thymoquinone, capsaicin and quercetin were applied to four human colorectal cancer cell lines HT-29, Caco-2, Lim-1215 and Lim-2405 in combination with platinum drugs cisplatin and oxaliplatin using three sequences of administration (0/0 h, 0/4 h and 4/0 h). Activity of compounds alone and in combination were determined using MTT reduction assay. Combination index was used as a measure of combined drug action. Studies on cellular accumulation, platinumDNA binding, DNA damage and proteomics were carried out to obtain mechanistic insights. In HT-29 cell line all sequences of administration produced antagonism at lower concentration (ED50). In Caco-2 cell line, bolus combination of cisplatin with resveratrol was found to produce moderate synergistic effect at all concentrations. In Lim-2405 cell line, combination of cisplatin with quercetin was found to produce most synergistic outcome. As applied to oxaliplatin, its combination with quercetin was found to produce most synergistic outcomes in Caco-2 cell line. Combination of oxaliplatin and capsaicin was most synergistic in Lim-2405 cell line. Results on PtDNA binding showed that synergistic effect was associated with higher platinumDNA binding. In proteomics study, 16 proteins belonging to different functional groupings were found to undergo changes in expression as a result of treatment with synergistic combinations.