Synergism from Combination between Platinums and Phytochemicals in Ovarian Cancer Cell Lines

Abstract

Ovarian cancer remains an on-going challenge because o f the occurrence o f resistant forms of cancer for which the drugs fail to function. Combination chemotherapy using drugs with different mechanisms can offer a means of overcoming drug resistance. In this study, binary combinations of four platinums: cisplatin (CS), YH12 which is iratts-(ammine)[imidazo(l,2- pyridinejdichloroplatinum (II) further abbreviated as YH, TH1 which is [{trans- PtCl(NH3)2}2{ira«5-Pt(3-hydroxypyridine)2(H2NCH2)6NH2)2}]Cl4 further abbreviated as TH, oxaliplatin (OX) and six phytochemicals: paclitaxel (Tax), colchicine (Col), curcumin (Cur), epigallocatechin-3-gallate (Egcg), chlorophyllin (Chi) and andrographolide (Andro) were applied to three human ovarian cancer cell lines A2780, A2780cisR and A2780ZU0473R as a function of concentration and the sequence of addition. Both the dose effect curves and combination indices show that the binary combinations o f platinums with phytochemicals show concentration- and sequencedependent 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 and 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 o f addition i.e. the variation in the extent o f cell kill with the change in sequence o f addition clearly indicates that the action o f one drug modulates that of the other (towards the induction of apoptosis). It is found that generally higher the degree o f synergism, the higher are the levels of intracellular platinum accumulation and Pt-DNA binding. Proteomic studies have identified five proteins namely TCTP, RSSA Human, MARE 1 HUMAN, ANXA5, ATPB, that are believed to be associated with platinum resistance in ovarian cancer cell line A2780clsR. 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. XII