[Reduced intracellular drug accumulation related to overexpression of P-glycoprotein cannot explain the complete drug resistance in MDR cell variant K562/Dox].
The purpose of this study was to determine what proportion of drug resistance of MDR cell variant K562/Dox was attributed to the reduced steady state intracellular drug accumulation related to overexpression of P-glycoprotein. K562/Dox was derived from repeated exposure of human erythroleukaemic cell line K562 cell to doxorubicin. As assessed with MTT assay, the resistance of K562/Dox to 7 cytotoxic drugs increased variably in the range between 1200 and 11 folds. K562/Dox cells were positively stained with anti-human p-glycoprotein monoclonal antibody JSB-1, indicating overexpression of P-gp. Intracellular drug accumulation in K562/Dox, though significantly reduced as compared with that in K562 cells, was maximally restored by concurrent exposure of cells to 6 mumol/L verapamil and 1.72 mumol/L either of the doxorubicin, epirubicin or daunorubicin. Similar results were obtained by exposure of cells to 12 mumol/L verapamil and 8.62 mumol/L drug, indicating that restoration of intracellular drug accumulation in MDR cells was dependent on the relative concentrations of verapamil to drug. However, the resistances of K562/Dox cells to epirubicin and daunorubicin still remained for about 5.6 and > 6.6 folds, respectively, even at verapamil concentration of 6 mumol/L, suggesting at least a relatively big fraction of drug resistance was not directly related to the altered cellular pharmacokinetics associated with overexpression of P-glycoprotein.
Hu
X
X
Cancer Institute, Zhejiang Medical University, Hangzhou.
Pan
Q
Q
Zheng
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003630:Daunorubicin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D015251:Epirubicin / Q000494:pharmacology; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000737:chemistry
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D015251:Epirubicin; D004317:Doxorubicin; D003630:Daunorubicin