Distinct groups of multidrug resistance modulating agents are distinguished by competition of P-glycoprotein-specific antibodies.
P-glycoprotein (Pgp) is one of the ABC transporters responsible for the multidrug resistance of cancer cells. The conformational changes of Pgp that occur in the presence of substrates/modulators or ATP depletion are accompanied by the up-shift of UIC2 monoclonal antibody (mAb) binding. In the case of cyclosporin A, vinblastine or valinomycin, this up-shift was found to be concomitant with the near-complete suppression of labeling with other mAbs specific for Pgp epitopes overlapping with UIC2, while pre-treatment with verapamil or Tween 80 brings about a modest suppression. Here we have extended these observations to 44 Pgp interacting agents, and found that only 8 fall into the cyclosporin-like category, inducing a conformational state characterized by the complete UIC2 dominance. The rest of the drugs either did not affect antibody competition or had a modest effect. Thus, Pgp substrates/modulators can be classified into distinct modalities based on the conformational change they elicit.
Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary.
Henrietta
H
Nagy
Katalin
K
Goda
Ferenc
F
Fenyvesi
Zsolt
Z
Bacsó
Mária
M
Szilasi
János
J
Kappelmayer
György
G
Lustyik
Maurizio
M
Cianfriglia
Gábor
G
Szabó
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology; D003902:Detergents / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics* / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005434:Flow Cytometry; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D007559:Ivermectin / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D003902:Detergents; D005452:Fluoresceins; D007559:Ivermectin; D016572:Cyclosporine; D000251:Adenosine Triphosphatases; C007740:fluorexon