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

Previous studies have shown that multidrug resistance (MDR) in the dox orubicin-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 r eport that resistance to daunorubicin, vincristine and rhodamine 123 c an be partially reversed in these cell lines by exposing the cells to buthionine sulphoximine (BSO), an inhibitor of glutathione (GSH) synth esis. This effect of BSO on drug resistance was associated with an inc reased intracellular accumulation of daunorubicin and rhodamine 123, o wing to inhibition of the enhanced drug efflux. In contrast, the accum ulation of daunorubicin was not increased by BSO treatment in a P-glyc oprotein (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 additio n, increase of cellular GSH levels in BSO-treated COR-L23/R and GLC4/A DR cells as a result of incubation with 5 mM GSH ethyl ester restored the accumulation deficit of daunorubicin. However, the transport of da unorubicin 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.