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 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.


METHODS
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.


CONCLUSIONS
Pgp inhibitory agents have differential effects on MRP-derived drug resistance which could be exploited in treatment of multidrug resistance in cancer patients.
Lehne
G
G
Department of Clinical Pharmacology, Institute for Surgical Reseach, The National Hospital, Rikshospitalet, University of Oslo, Norway.
Mørkrid
L
L
den Boer
M
M
Rugstad
H E
HE
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D003630:Daunorubicin / Q000378:metabolism*; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005453:Fluorescence; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D003524:Cyclosporins; D003986:Dibenzocycloheptenes; D010456:Peptides, Cyclic; D011804:Quinolines; C072534:SDZ 280 446; C095179:zosuquidar trihydrochloride; C070272:valspodar; D003630:Daunorubicin