Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for cyclosporine.
The immunosuppressive agent cyclosporine A (CSA) has been shown to reverse multidrug resistance (MDR) in malignant cells. In the present study, a 3H-cyclosporine diazirine analogue (3H-PL-CS) was used to photolabel viable MDR 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.
Ryffel
B
B
Sandoz Pharma Ltd., Basel, Switzerland.
Woerly
G
G
Rodriguez
C
C
Foxwell
B M
BM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D003524:Cyclosporins / Q000378:metabolism*; D004351:Drug Resistance / Q000502:physiology*; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism; D010641:Phenotype; D011233:Precipitin Tests; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins