Inhibition by arsenite of anticancer drug cis-diamminedichloroplatinum(II) induced DNA repair and drug resistance in HeLa cells

We have previously reported a cisplatin-resistant HeLa variant cell line (HeLa/CPR) which exhibited an enhancement in repairing cisplatin-DNA adducts (Chao, 1994, Mol.Pharmacol. 45, 1137-1144). In this study, using this cell line, we investigated the modification, by arsenite, of cisplatin-induced cytotoxicity and DNA repair in the resistant cell line. By a sublethal dose of arsenite, cytotoxicity of the resistant cells was enhanced by 2.5-fold, compared to 1.62-fold in the parental cells. Using enzyme-linked immunosorbent assay (ELISA) and a monoclonal antibody specific for cisplatin-DNA adducts, we found that the resistant cells showed a 5.15-fold decrease in the adduct formation compared to the parental cells. However, in the presence of arsenite, the resistant cells showed only a 1.47-fold decrease in the adduct formation, indicating a more than 3-fold modification. Using host cell reactivation of transfected plasmid DNA carrying cisplatin damage (an indirect detection of DNA repair), arsenite also revealed a ∼ 2-fold modification of adduct formation in the resistant cells. In addition, the time-dependent potentiation of cytotoxicity by arsenite in both cell lines was parallel to the increase of adduct formation. These results indicate that arsenite is an effective modifier of cisplatin-induced resistance and enhanced DNA repair in HeLa/CPR cells. The results are consistent with the notion that the cisplatin-resistant phenotype in HeLa cells is mainly mediated by enhancement of DNA repair.