The Relationship Between Modulation of MDR and Glutathione in MRP-Overexpressing Human Leukemia Cells

• Published in: Biochemical pharmacology 1998-04, Vol.55 (8), p.1283-1289
• Main Authors: Grech, Karen V., Davey, Ross A., Davey, Mary W.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; ATP-Binding Cassette Transporters - biosynthesis; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Buthionine Sulfoximine - pharmacology; Cell Division - drug effects; Daunorubicin - pharmacology; Drug Resistance, Multiple - genetics; Drug Resistance, Multiple - physiology; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - physiology; Etoposide - pharmacology; Gene Expression Regulation, Neoplastic; General aspects; Genes, MDR; glutathione; Glutathione - metabolism; Humans; Leukemia; Medical sciences; multidrug resistance; multidrug resistance-associated protein; Multidrug Resistance-Associated Proteins; P-glycoprotein; Pharmacology. Drug treatments; SDZ PSC 833; Tumor Cells, Cultured; verapamil
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(97)00562-5

Multidrug resistance-associated protein (MRP) causes multidrug resistance (MDR) involving the anthracyclines and epipodophyllotoxins. Many studies 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-glycoprotein-expressing cells. Etoposide accumulation was 50% reduced in both the CEM/E1000 MRP-overexpressing subline and the CEM/VLB 100 P-glycoprotein-expressing subline compared to the parental CEM cells, correlating with similar resistance to etoposide (200-fold) of the two sublines. For the CEM/VLB 100 subline, the P-glycoprotein inhibitor SDZ PSC 833, but not verapamil, was able to increase etoposide accumulation and cytotoxicity. For the CEM/E1000 subline, neither SDZ PSC 833 nor verapamil had any effect on etoposide accumulation. However, verapamil caused a 4-fold sensitization to etoposide in this subline, along with an 80% decrease in cellular glutathione ( P < 0.05). Buthionine sulfoximine (BSO), which depletes glutathione, also caused a 2.5-fold sensitization to etoposide with no effect on accumulation in the CEM/E1000 subline. In contrast, SDZ PSC 833 was able to increase daunorubicin accumulation in the CEM/E1000 subline ( P < 0.05), but had no effect on daunorubicin cytotoxicity, or cellular glutathione. These results show that modulation of etoposide cytotoxicity in MRP-overexpressing cells may be through changes in glutathione metabolism rather than changes in accumulation and confirm that changes in drug accumulation are not related to drug resistance in MRP-overexpressing cells.