Relationship between the inhibition of azidopine binding to P-glycoprotein by MDR modulators and their efficiency in restoring doxorubicin intracellular accumulation.
Using three different cell lines exhibiting the MDR phenotype, we have studied the ability of eight different modulators to restore doxorubicin intracellular accumulation and to inhibit azidopine binding to membrane extracts. One cell line was of human origin (KB VI) and two of murine origin, overexpressing two different isoforms of the mdrl gene (C6 IV and C6 0.5). The modulators were distributed in different drug classes: cyclosporine A and PSC-833, quinine and quinidine, nifedipine and nicardipine, and verapamil and S-9788. We observed that there was no strict parallelism between restoration of doxorubicin intracellular accumulation and inhibition of azidopine binding. However, when considering separately each group of drugs, it appeared that the most potent drug in inhibiting azidopine labelling of P-glycoprotein (P-gp) was also the most potent in restoring doxorubicin accumulation. This indicates that azidopine binding cannot be used as a general screening test for the identification of new modulators, but rather at the level of the selection of potent analogues within a chemical family. The three cell lines behaved similarly, indicating that the structural diversity of P-pgs did not influence the efficiency and binding of modulators.
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Institut Bergonié and University of Bordeoux II, France.
Chapey
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Robert
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000345:Affinity Labels / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001386:Azides / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004095:Dihydropyridines / Q000378:metabolism*; D004317:Doxorubicin / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D006801:Humans; D051379:Mice; D009529:Nicardipine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D001386:Azides; D003524:Cyclosporins; D004095:Dihydropyridines; D010880:Piperidines; D014227:Triazines; C077022:S 9788; C041130:azidopine; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; D009529:Nicardipine; C070272:valspodar