Circumvention of daunorubicin resistance by a new tamoxifen derivative, toremifene, in multidrug-resistant cell line.
The reversing effect of toremifene, a new tamoxifen derivative, on multidrug resistance in a K562 subline and its mechanism were studied. K562 cells were cultured in serially increasing concentrations up to 1.0 microM daunorubicin (DNR), and were found to be 28 times more resistant to DNR in comparison to the parent cells. In the resistant cell line (K562/D1-9), intracellular accumulation of DNR was less than that of the parent cell line, and P-glycoprotein was overexpressed. The resistance was reversed by addition of toremifene in a dose-dependent manner in K562/D1-9, while toremifene had no effect in K562. DNR accumulation was also reversed by toremifene in K562/D1-9, but not in K562. However, there was no significant difference of toremifene retention between K562/D1-9 and K562, and neither verapamil nor DNR increased toremifene accumulation in K562/D1-9. Moreover, toremifene and verapamil did not show an additive effect on intracellular DNR accumulation. These results suggested that the reversing mechanism of toremifene is different from that of verapamil, and this compound could be a good candidate for overcoming multidrug resistance.
Urasaki
Y
Y
First Department of Medicine, Fukui Medical School.
Ueda
T
T
Nakamura
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins / Q000235:genetics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003630:Daunorubicin / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D010641:Phenotype; D012995:Solubility; D017312:Toremifene / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D017312:Toremifene; D014700:Verapamil; D003630:Daunorubicin