Synergism from combinations of platinums with phytochemicals as applied to ovarian cancer

Fazlul Huq
School of Medical Sciences, Sydney Medical School, The University of Sydney, Sydney, Australia

Abstract:

Combination chemotherapy using drugs with different mechanisms can offer a means of overcoming drug resistance. We have used binary combinations of cisplatin (CS), oxaliplatin (Ox) and designed platinums YH12, CH1 and TH1 and a number of phytochemicals including: paclitaxel (Tax), colchicine (Col), curcumin (Cur), epigallocatechin-3-gallate (Egcg), chlorophyllin (Chl), andrographolide (Andro), thymoquinone (Thy), resveratrol (Res) were applied to three human ovarian cancer cell lines A2780, A2780cisR and A2780ZD0473R as a function of concentration and the sequence of addition. Both the dose effect curves and combination indices show that the binary combinations of platinums with phytochemicals show concentration- and sequence-dependent synergism in the cell lines. Generally the degree of synergism is found to be greater in a sequenced addition than the bolus, with the 0/4 h addition often showing the strongest synergism. Among the platinums, cisplatin is found to produce greatest synergistic outcomes in combination with phytochemicals while YH12 produces the least. Among the phytochemicals, Col has produced the most synergistic outcomes in combination with platinums and Andro has produced the least. The change in synergism with the change in sequence of addition clearly indicates that the action of one drug modulates that of the other (towards the induction of apoptosis). It is found that generally higher the degree of synergism, the higher are the levels of intracellular platinum accumulation and Pt-DNA binding. Proteomic studies have identified five proteins namely TCTP, RSSA Human, MARE1_HUMAN, ANXA5, ATPB, that are believed to be associated with platinum resistance in ovarian cancer cell line A2780cisR. Synergistic combination of CS and Tax is found to restore expressions of TCTP and ATPB, that of CS and Col is found to restore expressions of ANXA5 and ATPB, and that of CS and Egcg is found to restore expressions of TCTP and ANXA5.