REGULATION BY GLUTATHIONE OF DRUG TRANSPORT IN MULTIDRUG-RESISTANT HUMAN LUNG-TUMOR CELL-LINES OVEREXPRESSING MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN

被引：220

作者：

VERSANTVOORT, CHM

BROXTERMAN, HJ

BAGRIJ, T

SCHEPER, RJ

TWENTYMAN, PR

机构：

[1] FREE UNIV AMSTERDAM HOSP,DEPT MED ONCOL,AMSTERDAM,NETHERLANDS

[2] FREE UNIV AMSTERDAM HOSP,DEPT PATHOL,AMSTERDAM,NETHERLANDS

来源：

BRITISH JOURNAL OF CANCER | 1995年 / 72卷 / 01期

关键词：

MULTIDRUG RESISTANCE; MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP); GLUTATHIONE; BUTHIONINE SULFOXIMINE (BSO); DRUG TRANSPORT;

D O I：

10.1038/bjc.1995.281

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Previous studies have shown that multidrug resistance (MDR) in the doxorubicin-selected lung tumour cell lines COR-L23/R, GLC4/ADR and MOR/R is associated with overexpression of the MRP gene. In this study we report that resistance to daunorubicin, vincristine and rhodamine 123 can be partially reversed in these cell lines by exposing the cells to buthionine sulphoximine (BSO), an inhibitor of glutathione (GSH) synthesis. This effect of BSO on drug resistance was associated with an increased intracellular accumulation of daunorubicin and rhodamine 123, owing to inhibition of the enhanced drug efflux. In contrast, the accumulation of daunorubicin was not increased by BSO treatment in a P-glycoprotein (P-gp)-mediated MDR cell line. BSO treatment (25 mu M, 20 h) of the cell lines resulted in 60-80% depletion of cellular GSH levels. The effects of BSO on daunorubicin accumulation in the COR-L23/R and GLC4/ADR cells were associated with cellular GSH depletion. In addition, increase of cellular GSH levels in BSO-treated COR-L23/R and GLC4/ADR cells as a result of incubation with 5 mM GSH ethyl ester restored the accumulation deficit of daunorubicin. However, the transport of daunorubicin did not increase the GSH release in any of the cell lines. These results demonstrate that drug transport in MRP- but not in P-gp-overexpressing MDR tumour cell lines can be regulated by intracellular GSH levels.

引用

页码：82 / 89

页数：8

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