PSC833, cyclosporin A, and dexniguldipine effects on cellular calcein retention and inhibition of the multidrug resistance pump in human leukemic lymphoblasts.
A convenient functional assay of the multidrug resistance (MDR) pump is useful for the diagnosis of MDR-1 cancers and the quantitative determination of the potency of inhibitors of the pump. Calcein-AM, a substrate of the MDR pump, was used to determine the concentration of SDZ PSC833 needed to completely inhibit the pump in CEM/VLB100 drug-resistant cells. The initial rates (in percent) for calcein retention by these MDR-1 cells were used to calculate values for the percent initial efflux of calcein-AM through the MDR pump in the presence of the inhibitors PSC833, cyclosporinA, and dexniguldipine. The percent efflux values at 250 and 60 nM calcein-AM were used to calculate the required concentration of each inhibitor to produce half-inhibition (I50) of initial efflux through the pump. These results are consistent with a noncompetitive inhibition of the MDR pump by each of the three inhibitors.
Wigler
P W
PW
Department of Medical Biology, University of Tennessee Medical Center, 1924 Alcoa Highway, Knoxville, Tennessee, 37920, USA. paulwig@yahoo.com
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005452:Fluoresceins / Q000378:metabolism* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007938:Leukemia / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008970:Molecular Weight; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D004095:Dihydropyridines; D005452:Fluoresceins; C085925:calcein AM; D016572:Cyclosporine; C070272:valspodar; C054074:niguldipine