Small molecules that dramatically alter multidrug resistance phenotype by modulating the substrate specificity of P-glycoprotein.
By screening a chemical library for the compounds protecting cells from adriamycin (Adr), a series of small molecules was isolated that interfered with the accumulation of Adr in mouse fibroblasts by enhancing efflux of the drug. Isolated compounds also stimulated efflux of Rhodamine 123 (Rho-123), another substrate of multidrug transporters. Stimulation of drug efflux was detectable in the cells expressing P-glycoprotein (P-gp), but not in their P-gp-negative variants, and was completely reversible by the P-gp inhibitors. A dramatic stimulation of P-gp activity against Adr and Rho-123 by the identified compounds was accompanied by suppression of P-gp-mediated efflux of other substrates, such as Taxol (paclitaxel) or Hoechst 33342, indicating that they act as modulators of substrate specificity of P-gp. Consistently, P-gp modulators dramatically altered the pattern of cross-resistance of P-gp-expressing cells to different P-gp substrates: an increase in resistance to Adr, daunorubicin, and etoposide was accompanied by cell sensitization to Vinca alkaloids, gramicidin D, and Taxol with no effect on cell sensitivity to colchicine, actinomycin D, puromycin, and colcemid, as well as to several non-P-gp substrates. The relative effect of P-gp modulators against different substrates varied among the isolated compounds that can be used as fine tools for analyzing mechanisms of drug selectivity of P-gp. These results raise the possibility of a rational control over cell sensitivity to drugs and toxins through modulation of P-gp activity by small molecules.
Kondratov
R V
RV
Department of Molecular Genetics, University of Illinois, Chicago, IL 60607, USA.
Komarov
P G
PG
Becker
Y
Y
Ewenson
A
A
Gudkov
A V
AV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010641:Phenotype; D020112:Rhodamine 123 / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D007093:Imidazoles; C442830:QB 102; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D020112:Rhodamine 123; D004317:Doxorubicin