Establishment of an arsenic trioxide-resistant human leukemia cell line that shows multidrug resistance.
We have established an arsenic trioxide (As2O3)-resistant cell line (K562/AS-3) derived from the human leukemia cell line K562. K562/AS-3 was sequentially cultured with increasing concentrations of As2O3 up to 3.5 microM and then cloned by the limiting dilution method. K562/AS-3 was found to be about 7-fold more resistant to As2O3 than the parent cells (IC50=12.9 microM for K562/AS-3 and 1.8 microM for K562), and also showed cross resistance to VP-16 and vincristine. The multidrug resistance-associated protein (MRP1) gene was found to be overexpressed, but the MDR gene was not detected. MRP1 function was evaluated by measuring calcein acetoxymethyl ester (calcein-AM) efflux, and by verifying its inhibition by MK571, a potent MRP inhibitor. In addition, an increase of the total intracellular glutathione content was found in K562/AS-3. The resistance of K562/AS-3 to As2O3 was reversed by the addition of MK571, but not by verapamil. K562/AS-3 may be useful for studying the mechanism of the anticancer effect of As2O3 and how to overcome As2O3-resistance.
Seo
Tamami
T
First Department of Internal Medicine, University of Fukui, Fukui, Japan.
Urasaki
Yoshimasa
Y
Ueda
Takanori
T
D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000166:cytology*; D002999:Clone Cells; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis; D010087:Oxides / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D000077237:Arsenic Trioxide; D001152:Arsenicals; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010087:Oxides; D014750:Vincristine; C421109:multidrug resistance-associated protein 1