Comparative effect of verapamil, cyclosporin A and SDZ PSC 833 on rhodamine 123 transport and cell cycle in vinblastine-resistant Chinese hamster ovary cells overexpressing P-glycoprotein.
The product of the mdr1 gene, P-glycoprotein (P-gp), represents a common mechanism of cellular resistance to a wide variety of structurally and functionally unrelated drugs. A range of structurally different P-gp inhibitors, such as verapamil, cyclosporin A and SDZ PSC 833, have been shown to modify multidrug resistance (MDR). We used flow cytometry to investigate in vitro modulation of P-gp-dependent efflux of rhodamine 123 (Rh123). The capacity to modulate the MDR phenotype of vinblastine-resistant Chinese hamster ovary (CHO) cells was assessed by analyzing the concentration of modulator needed to decrease the Rh123 mean fluorescence intensity by 50%. We found that the cyclosporin derivative SDZ PSC 833 was significantly more effective than cyclosporin A and verapamil, either in the presence or absence of fetal calf serum-supplemented media. This study indicates that analysis of Rh123 efflux modulation can be used to determine the optimal doses of MDR inhibitors in vitro and suggests that more than one modulator is needed to measure P-gp function, since verapamil had no effect on Rh123 modulation when MDR cells were used.
Pétriz
J
J
Departament de Criobiologia i Teràpia Cellular, Institut de Recerca Oncològica, Hospital Duran i Reynals, Barcelona, Spain.
Sánchez
J
J
Bertrán
J
J
García-López
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D012235:Rhodamines; D020112:Rhodamine 123; D014747:Vinblastine; D016572:Cyclosporine; D004247:DNA; D014700:Verapamil; C070272:valspodar