The absence of stereoselective P-glycoprotein- and multidrug resistance-associated protein-mediated transport of daunorubicin.
Multidrug resistance phenotype in mammalian cells is often correlated with overexpression of P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP1). Both proteins are energy-dependent drug efflux pumps that efficiently reduce the intracellular accumulation and hence the cytotoxicity of many natural cytotoxins. Thus, both P-gp and MRP1 proteins are able to transport anthracycline but the role of chirality has not, up to now, been addressed. In this study, we compared the P-gp- and MRP1-mediated efflux of daunorubicin and its enantiomer WP900 in multidrug-resistant cells overexpressing either P-gp (K562/ADR cells) or MRP1 (GLC4/ADR cells). Using fluorescence techniques, we showed that in both cell lines the presence of the pump yielded a gradient of drug concentration: the intracellular free drug concentration in the cytosol was lower than the extracellular free drug concentration. Our data showed that the gradient of concentration generated by the pump was the same whether DNR or WP900 was used. This means that P-gp on the one hand and MRP1 on the other recognise WP900 as well as DNR and that the chirality of the molecule plays no role.
Loetchutinat
C
C
Laboratoire de Physicochimie Biomoleculaire et Cellulaire, UMR 7033, Université Paris Nord, Bobigny, France.
Heywang
C
C
Priebe
W
W
Garnier-Suillerot
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics*; D004351:Drug Resistance / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D008968:Molecular Conformation; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D004247:DNA; D003630:Daunorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins