Multidrug Resistance-Associated Protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine Sulfoximine

Cancer Cell International

Tomris Ozben¹  Burhan Savas³  Hakan Akca²  Selma Akan¹  Ilhan Akan¹ 

[1] Akdeniz University, Faculty of Medicine, Department of Biochemistry, 07070 Antalya, Turkey;Pamukkale University, Faculty of Art&Science, Department of Biology, Denizli, Turkey;Akdeniz University, Faculty of Medicine, Department of Internal Medicine, Division of Oncology, 07070 Antalya, Turkey

关键词: GSH;    BSO;    N-acetylcysteine;    HEK293;    vincristine;    MRP1;   

Others  :  795984
DOI  :  10.1186/1475-2867-5-22

 received in 2005-05-05, accepted in 2005-07-24,  发布年份 2005

【 摘 要 】

Background

Multidrug resistance mediated by the multidrug resistance-associated protein 1 (MRP1) decreases cellular drug accumulation. The exact mechanism of MRP1 involved multidrug resistance has not been clarified yet, though glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-Buthionine (S,R)-sulfoximine (BSO) is an inhibitor of GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO on MRP1-mediated vincristine resistance in Human Embryonic Kidney (HEK293) and its MRP1 transfected 293MRP cells. Human Embryonic Kidney (HEK293) cells were transfected with a plasmid encoding whole MRP1 gene. Both cells were incubated with vincristine in the presence or absence of NAC and/or BSO. The viability of both cells was determined under different incubation conditions. GSH, Glutathione S-Transferase (GST) and glutathione peroxidase (GPx) levels were measured in the cell extracts obtained from both cells incubated with different drugs.

Results

N-acetylcysteine increased the resistance of both cells against vincristine and BSO decreased NAC-enhanced MRP1-mediated vincristine resistance, indicating that induction of MRP1-mediated vincristine resistance depends on GSH. Vincristine decreased cellular GSH concentration and increased GPx activity. Glutathione S-Transferase activity was decreased by NAC.

Conclusion

Our results demonstrate that NAC and BSO have opposite effects in MRP1 mediated vincristine resistance and BSO seems a promising chemotherapy improving agent in MRP1 overexpressing tumor cells.

【 授权许可】

   
2005 Akan et al; licensee BioMed Central Ltd.

【 图 表 】

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