Interaction of combinations of drugs, chemosensitizers, and peptides with the P-glycoprotein multidrug transporter.
P-Glycoprotein functions as an ATP-driven efflux pump for hydrophobic natural products and peptides, and gives rise to resistance to multiple chemotherapeutic drugs. The inhibition of colchicine transport via P-glycoprotein by various compounds was determined in a plasma membrane vesicle model system. A chemotherapeutic drug (vinblastine) and several chemosensitizers (verapamil, reserpine, cyclosporin A) and hydrophobic peptides (N-acetyl-leucyl-leucyl-methioninal, leupeptin, pepstatin A, valinomycin) were examined, both as individual species and as combinations of compounds. The median effect analysis was used to determine the concentration of each combination required to produce a median effect, Dm, as well as the sigmoidicity of the concentration-effect plot, m. The combination of cyclosporin A and verapamil was the only one established to be mutually nonexclusive, whereas several mutually exclusive pairs of compounds were identified. The combination index, CI, was calculated for several combinations of drugs, chemosensitizers, and peptides, and used to ascertain whether effects were synergistic, antagonistic, or additive. Some combinations (vinblastine/verapamil; verapamil/valinomycin) showed antagonism over the entire concentration range. Other combinations (valinomycin/N-acetyl-leucyl-leucyl-methioninal; cyclosporin A/verapamil) displayed both synergism and antagonism over different regions of the CI plot. Many combinations of compounds displayed additive interactions over most of the CI plot. The median effect analysis may be helpful in identifying potentially useful additive or synergistic combinations of compounds for reversal of Pgp-mediated drug resistance.
DiDiodato
G
G
Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry and Biochemistry, University of Guelph, ON, Canada.
Sharom
F J
FJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003078:Colchicine / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D007976:Leupeptins / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D012110:Reserpine / Q000494:pharmacology; D014634:Valinomycin / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007976:Leupeptins; D009842:Oligopeptides; D010455:Peptides; C069861:calpain inhibitor 2; D014634:Valinomycin; D014747:Vinblastine; D016572:Cyclosporine; D012110:Reserpine; C032854:leupeptin; D003078:Colchicine