Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance protein (MRP)
G. Lehne1,2, L. Mrrkrid3, M. den Boer4, H.E. Rugstad1
1 Department of Clinical Pharmacology, 2 Institute for Surgical Research, 3 Department of Clinical Chemistry, The National Hospital, Rikshospitalet, University of Oslo, Norway, and 4 Department of Pediatrics, Free University Hospital, Amsterdam, The Netherlands
DOI 10.5414/CPP38187
Abstract
Multidrug resistance (MDR) to cancer chemotherapy is frequently associated with decreased drug accumulation in cancer cells due to drug expulsion by multidrug 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, and their MRP inhibitory potential is largely unknown. Objective: In the present study we addressed the effect of these agents on MRP-derived drug resistance. Materials: Drug-resistant human leukemia cells with Pgp+/MRP– (KG1a/200, K562/150) and Pgp–/MRP+ (HL60/130) phenotypes were maintained in suspension cultures for experimental studies of drug accumulation and drug sensitization by Pgp inhibitors. Methods: Intracellular accumulation of the fluorescent anthracycline daunorubicin was measured by flow cytometry and fluorescence detection. Daunorubicin dose-response curves were generated by non-linear regression of electronically measured cell counts of 72- – 96-h cultures. The half-maximal growth inhibitory dose (GI50) was used as measure of growth inhibition. 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 did not affect accumulation of daunorubicin in Pgp–/MRP+ cells nor sensitize these cells to daunorubicin. Conclusion: Pgp inhibitory agents have differential effects on MRP-derived drug resistance which could be exploited in treatment of multidrug resistance in cancer patients.
Author Details
Authors
Departments
- 1 Department of Clinical Pharmacology,
- 2 Institute for Surgical Research,
- 3 Department of Clinical Chemistry, The National Hospital, Rikshospitalet, University of Oslo, Norway, and
- 4 Department of Pediatrics, Free University Hospital, Amsterdam, The Netherlands
Address
Dr. G. Lehne; Department of Clinical Pharmacology, Rikshospitalet, The National Hospital of Norway, N-0027 Oslo
Citation
G. Lehne, L. Mrrkrid, M. den Boer and H.E. Rugstad.Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance protein (MRP). 2000; 38: 187-195. doi: 10.5414/CPP38187.
