Overcoming of multidrug resistance by introducing the apoptosis gene, bcl-Xs, into MRP-overexpressing drug resistant cells

Multidrug resistance associated protein (MRP) is one of drug transport memb ranes that confer multidrug resistance in cancer cells. Multidrug resistanc e has been known to be associated with resistance to apoptosis. In this stu dy, using MRP overexpressing multidrug resistant nasopharyngeal cancer cell s, we examined the expression of apoptosis related genes including p53, p21 (WAFl), bax and bcl-Xs between drug sensitive KB and its resistant KB/7D ce lls. We also examined whether the introduction of apoptosis related gene co uld increase the sensitivity to anticancer drugs in association with apopto tic cell death. The relative resistances to anticancer drugs in KB/7D cells evaluated by IC50 values were 3.6, 61.3, 10.4 and 10.5 to adriamycin (ADM) , etoposide (VP-16), vincristine (VCR) and vindesine (VDS), respectively. T he resistance to anticancer drugs in KB/7D cells was associated with the at tenuation of internucleosomal DNA ladder formation in apoptosis. Of importa nt, the mRNA expression of bcl-Xs gene in KB/7D cells was decreased in one- fourth as compared to that of KB cells among the apoptosis genes. The mRNA expression of bcl-Xs gene in a bcl-Xs transfected clone (KB/7Dbcl-Xs) was i ncreased about 2-fold compared to that of KB/7Dneo cells, while the mRNA ex pression of MRP gene was not significantly different in KB/7bcl-Xs and KB/7 Dneo cells. The sensitivities to anticancer drugs including ADM, VCR and VD S except VP-16 were increased in KB/7Dbcl-Xs cells, in turn, the relative r esistance in KB/7Dbcl-Xs cells was decreased to 1.4, 4.0, and 3.0 in ADM, V CR and VDS, respectively, as compared to those of KB/7Dneo cells. Of intere st, the studies on the accumulation of [H-3]VCR showed that the decrease of [3H]VCR accumulation in KB/7Dbcl-Xs was not significantly different from t hat of KB/7Dneo cells. Collectively, these results indicated that the mecha nism(s) of drug resistance in KB/7D cells could be explained at least by tw o factors: a) reduced drug accumulation mediated by MRP; b) resistance to a poptosis due to the decreased expression of the bcl-Xs gene. These results also indicated that the multidrug resistance mediated by MRP might be parti ally overcome by introducing apoptosis gene into drug resistant cells witho ut modulation of MRP function in drug accumulation.