Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance protein (MRP)

Multidrug resistance (MDR) to cancer chemotherapy is frequently associated with decreased drug accumulation in cancer cells due to drug expulsion by m ultidrug transporters such as P-glycoprotein (Pgp) and multidrug resistance protein (MRP). The novel resistance modifying agents PSC 833, 280-446. and LY 335979 are primarily targeted at inhibition of Pgp, acid their MRP inhi bitory potential is largely unknown, Objective: In the present study we add ressed the effect of these agents on MRP-derived drug resistance. Materials : Drug-resistant human leukemia cells with Pgp+/MRP- (KG1a/200, K562/150) a nd Pgp-/MRP+ (HL60/130) phenotypes were maintained in suspension cultures f or experimental studies of drug accumulation and drug sensitization by Pgp inhibitors. Methods: Intracellular accumulation of the fluorescent anthracy cline daunorubicin was measured by flow cytometry and fluorescence detectio n. Daunorubicin dose-response curves were generated by non-linear regressio n of electronically measured cell counts of 72- - 96-h cultures. The half-m aximal growth inhibitory dose (GI50) was used as measure of growth inhibiti on. Results: All MDR phenotypes studied exercised significant resistance to daunorubicin. PSC 833, 280-446 and LY335979 were equal in sensitizing Pgp/MRP- cells to daunorubicin-induced growth inhibition (p < 0.0001). The Pgp -/MRP+ cells responded to PSC 833 and 280-446 by increased accumulation of daunorubicin (p = 0.0022 and p = 0.0005, respectively) and sensitization to the drug (p = 0.0009 and p = 0.0007, respectively). Conversely, LY335979 d id not affect accumulation of daunorubicin in Pgp-/MRP+ cells nor sensitize these cells to daunorubicin. Conclusion: Pgp inhibitory agents have differ ential effects on MRP-derived drug resistance which could be exploited in t reatment of multidrug resistance in cancer patients.