THE RELATIONSHIP BETWEEN MODULATION OF MDR AND GLUTATHIONE IN MRP-OVEREXPRESSING HUMAN LEUKEMIA-CELLS

Multidrug resistance-associated protein (MRP) causes multidrug resista nce (MDR) involving the anthracyclines and epipodophyllotoxins. Many s tudies show modulation of anthracycline levels and cytotoxicity in MRP overexpressing cells, but there is limited data on the modulation of etoposide levels and cytotoxicity in MRP-overexpressing or in P-glycop rotein-expressing cells. Etoposide accumulation was 50% reduced in bot h the CEM/E1000 MRP-overexpressing subline and the CEM/VLB100 P-glycop rotein-expressing subline compared to the parental CEM cells, correlat ing with similar resistance to etoposide (200-fold) of the two subline s. For the CEM/VLB100 subline, the P-glycoprotein inhibitor SDZ PSC 83 3, but not verapamil, was able to increase etoposide accumulation and cytotoxicity. For the CEM/E1000 subline, neither SDZ PSC 833 nor verap amil had any effect on etoposide accumulation. However, verapamil caus ed a 4-fold sensitization to etoposide in this subline, along with an 80% decrease in cellular glutathione (P < 0.05). Buthionine sulfoximin e (BSO), which depletes glutathione, also caused a 2.5-fold sensitizat ion to etoposide with no effect on accumulation in the CEM/E1000 subli ne. In contrast, SDZ PSC 833 was able to increase daunorubicin accumul ation in the CEM/E1000 subline (P < 0.05), but had no effect on daunor ubicin cytotoxicity, or cellular glutathione. These results show that modulation of etoposide cytotoxicity in MRP-overexpressing cells may b e through changes in glutathione metabolism rather than changes in acc umulation and confirm that changes in drug accumulation are not relate d to drug resistance in MRP-overexpressing cells. (C) 1998 Elsevier Sc ience Inc.