The relationship between modulation of MDR and glutathione in MRP-overexpressing human leukemia cells

Biochem Pharmacol. 1998 Apr 15;55(8):1283-9. 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/VLB100 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/VLB100 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.

MeSH terms

  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / metabolism*
  • Antineoplastic Agents / pharmacology
  • 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
  • Genes, MDR
  • Glutathione / metabolism*
  • Humans
  • Leukemia
  • Multidrug Resistance-Associated Proteins
  • Tumor Cells, Cultured


  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Proteins
  • Buthionine Sulfoximine
  • Etoposide
  • Glutathione
  • Daunorubicin