P‐glycoprotein and alterations in the glutathione/glutathione‐peroxidase cycle underlie doxorubicin resistance in HL‐60‐R, a subclone of the HL‐60 human leukemia cell line

摘要: HL-60-R, a multi-drug-resistant (MDR) subclone of the human leukemia cell line HL-60, was selected in continuous culture doxorubicin (DOX) absence mutagenic agents. When compared to parent HL-60-R showed greater relative resistance vinblastine than etoposide, or selecting agent DOX. Co-exposure verapamil, known modulator MDR, partially increased its sensitivity DOX and vinblastine. The stained positively with P-glycoprotein-specific monoclonal antibody (MAb), C219, whereas HL-60 negative. Southern analysis 32-fold amplification mdrI gene slot-blot demonstrated 70-fold over-expression specific message HL-60. Northern blot revealed presence 2 species messenger RNA sizes 5.1 kb 4.5 kb. No transcripts were detectable parent. Flow cytometric significantly reduced cellular retention as well rapid efflux from drug-resistant line. proved be nearly 4 times more resistant hydrogen peroxide parent, 1,000 inhibition glutathione synthesis by D,L-buthionine sulfoximine (BSO). Verapamil modulated incompletely but, depletion, completely reversed resistance. Elevated levels glutathione-peroxidase activity demonstrated, thereby implicating enhanced glutathione/glutathione-peroxidase cycle an additional basis for These findings suggest that capacity detoxifying oxyradicals may contribute anthracycline acute leukemia.