TY - JOUR
T1 - Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance protein (MRP)
AU - Lehne, G
AU - Mørkrid, L
AU - den Boer, M
AU - Rugstad, H E
PY - 2000/4
Y1 - 2000/4
N2 - UNLABELLED: 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.
AB - UNLABELLED: 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.
KW - ATP Binding Cassette Transporter, Subfamily B/drug effects
KW - Antibiotics, Antineoplastic/metabolism
KW - Antineoplastic Agents/pharmacology
KW - Cyclosporins/pharmacology
KW - Daunorubicin/metabolism
KW - Dibenzocycloheptenes/pharmacology
KW - Drug Resistance, Multiple
KW - Drug Resistance, Neoplasm
KW - Flow Cytometry
KW - Fluorescence
KW - Humans
KW - Leukemia, Myeloid/metabolism
KW - Peptides, Cyclic/pharmacology
KW - Quinolines/pharmacology
KW - Tumor Cells, Cultured/drug effects
U2 - 10.5414/cpp38187
DO - 10.5414/cpp38187
M3 - Article
C2 - 10783828
SN - 0946-1965
VL - 38
SP - 187
EP - 195
JO - International journal of clinical pharmacology and therapeutics
JF - International journal of clinical pharmacology and therapeutics
IS - 4
ER -