Identification of the multidrug resistance-related P-glycoprotein as a cyclosporine binding protein.
The immunosuppressive agent cyclosporine A has been shown to reverse multidrug resistance (MDR) in malignant cells. In the present study, a 3H-cyclosporine diazirine analogue was used to photolabel viable MDR Chinese hamster ovary cells. The 170-kDa membrane P-glycoprotein, which functions as a drug efflux pump, was strongly labeled. The binding of 3H-cyclosporine diazirine analogue to P-glycoprotein was competable by excess cyclosporine A and by the nonimmunosuppressive cyclosporine H. These results suggest that cyclosporine reverses the MDR phenotype by binding directly to P-glycoprotein and that this binding is not dependent on the immunosuppressive potential of the cyclosporine derivative. The identification of P-glycoprotein as a cyclosporine binding protein has obvious implications for cancer chemotherapy.
Foxwell
B M
BM
Preclinical Research, Sandoz Ltd., Basle, Switzerland.
Mackie
A
A
Ling
V
V
Ryffel
B
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003524:Cyclosporins / Q000378:metabolism*; D004351:Drug Resistance; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008970:Molecular Weight; D011485:Protein Binding
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D002121:Calcium Channel Blockers; D003524:Cyclosporins; D008562:Membrane Glycoproteins