Factors contributing to the resistance to apoptosis induced by topoisomerase I inhibitors in vincristine resistant cells.

Abstract

The activity of numerous antineoplasic drugs is correlated with their capacity to induce the apoptotic process. In this study, apoptosis induced by the topoisomerase I (Topo I) inhibitors camptothecin (CPT) and the CPT-11 active metabolite SN-38 was evaluated on HL-60 cells and their multidrug resistant variant HL-60-Vincristine cells. Both CPT and SN-38 induced high levels of apoptosis in sensitive cells but very low levels in MDR cells. The role of the different genes and proteins usually implicated in the drug resistance phenomenon was studied. The Pgp independence of the two drugs was suggested by the lack of modulation of anti-Topo I effects with verapamil. Moreover CPT and SN-38 induced a strong decrease of mdr1 mRNA in MDR treated cells. MRP mRNA expression was very low in drug sensitive and resistant cells and decreased during treatments in both cell lines. However, MRP protein was not detected in control and MDR cells suggesting that this pump was probably not implicated in this resistance phenomenon. Topo I and BCL-2 proteins displayed a higher expression in MDR cells but only Topo I proteins decreased during treatments in the two cell lines. These data suggest that in addition to the classical multidrug resistance phenotype, dysregulation of proteins associated with DNA replication and apoptotic process could contribute to acquired resistance to a large panel of drugs, including those which are not considered as substrates for Pgp.