Multidrug resistance protein functionality: no effect of intracellular or extracellular pH changes.
A major problem in the treatment of cancer is cellular resistance to cytotoxic drugs. In tumor cells in vitro, the development of multidrug resistance is usually accompanied by increased expression of drug transporters, either P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP(1)). Both proteins belong to the superfamily of ATP-binding cassette (ABC) transporter proteins and mediate the transport of a broad range of drugs. Altenberg et al. (Proc Natl Acad Sci USA90: 9735-9738, 1993) have shown that changes in intra- or extracellular pH do not mediate P-gp-dependent multidrug resistance. Therefore, we similarly studied whether changes in intra- or extracellular pH could mediate MRP(1)-dependent multidrug resistance. In particular, we measured the MRP(1)-mediated efflux of hydroxyrubicin from GLC4/ADR cells. Since hydroxyrubicin is a fully neutral anthracycline derivative that has no deprotonable function at pH lower than 10 and so cannot accumulate in non-nuclear compartments under the influence of pH or transmembrane gradients, we hypothesized that any modifications of its kinetics of efflux as a function of pH can be assigned to a modification of the transporter efficiency. However, as our data show, modifications of extra- and/or intracellular pH yielded no modification of the MRP(1)-mediated efflux of hydroxyrubicin.
Marbeuf-Gueye
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C
Laboratoire de Physicochimie Biomoleculaire et Cellulaire, Universite Paris Nord, 93017, Bobigny, France.
Priebe
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W
Garnier-Suillerot
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D018432:Drug Resistance, Multiple / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015251:Epirubicin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D015251:Epirubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; C078444:MSH3 protein, human; C042907:3'-deamino-3'-hydroxydoxorubicin; C421109:multidrug resistance-associated protein 1