P-glycoprotein-mediated efflux of hydroxyrubicin, a neutral anthracycline derivative, in resistant K562 cells.
Hydroxyrubin (OH-Dox), a neutral doxorubicin derivative that is only slightly cross-resistant to doxorubicin (Dox), can be actively pumped out of resistant K562 cells by P-glycoprotein (P-gp). This efflux is saturable and can be inhibited by verapamil. The Michaelis constant is equal to 2 +/- 0.5 microM. However, the efficiency of P-gp in pumping out the drugs is 2.5 times less for OH-Dox than for Dox. This shows that in order to be pumped out by P-gp a molecule does not necessarily have to have a basic center. The mean influx coefficient for the drug is 5 times higher for OH-Dox than for Dox. In conclusion, the degree of resistance of analogs is related not only to their ability to be recognized and transported by P-gp but also, and probably essentially, to their kinetics of uptake. Both parameters have to be taken into account in the rational design of new compounds capable of overcoming multidrug resistance.
Borrel
M N
MN
Laboratoire de Chimie Bioinorganique (LPCB URA 198 CNRS), Université Paris Nord, Bobigny, France.
Fiallo
M
M
Priebe
W
W
Garnier-Suillerot
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D002460:Cell Line; D002999:Clone Cells; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004351:Drug Resistance; D015251:Epirubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute; D015394:Molecular Structure; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015251:Epirubicin; C042907:3'-deamino-3'-hydroxydoxorubicin; D004317:Doxorubicin; D005947:Glucose