Comparison of drug accumulation in P-glycoprotein-expressing and MRP-expressing human leukaemia cells.
P-glycoprotein- and multidrug resistance-associated protein (MRP)-mediated multidrug resistance is associated with decreased drug accumulation. The P-glycoprotein-expressing CCRF-CEM/VLB100 subline and the MRP-expressing CCRF-CEM/E1000 subline are both 50-fold resistant to daunorubicin. However, accumulation of daunorubicin and rhodamine 123 was > 85% reduced in the P-glycoprotein-expressing subline compared to 40-50% in the MRP-expressing subline. Further, the CCRF-CEM/E1000 cells were 30-fold resistant to idarubicin, without reduced accumulation. Verapamil and SDZ PSC 833 restored daunorubicin and rhodamine 123 accumulation, while buthionine sulphoximine affected only the CCRF-CEM/ E1000 subline. We conclude that the verapamil associated change in rhodamine 123 accumulation provides a sensitive functional assay for both P-glycoprotein- and MRP-mediated MDR.
Neurobiology Unit, University of Technology, Sydney, NSW, Australia. M.Davey@uts.edu.au
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D003630:Daunorubicin / Q000378:metabolism*; D006801:Humans; D015255:Idarubicin / Q000378:metabolism*; D015458:Leukemia, T-Cell / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D019328:Buthionine Sulfoximine; D002121:Calcium Channel Blockers; D003524:Cyclosporins; D003630:Daunorubicin; D015255:Idarubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020112:Rhodamine 123; D012235:Rhodamines; D014700:Verapamil; C070272:valspodar