Abstract
BackgroundMultidrug 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.ResultsN-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.ConclusionOur 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.
Highlights
Multidrug resistance mediated by the multidrug resistance-associated protein 1 (MRP1) decreases cellular drug accumulation
The exact mechanism of MRP1 involved multidrug resistance remains unknown, GSH is likely to have a role for the resistance to occur
Effects of NAC on vincristine cytotoxicity The viability of HEK293 and 293MRP cells treated with vincristine was significantly lower than the respective untreated control cells (11.4 ± 2.3% and 52.4 ± 5.2% respectively, p < 0.5) (Fig 3). 293MRP cells were more resistant to vincristine than HEK293 cells
Summary
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. 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. Two proteins are well-known for causing MDR Both proteins, the MDR1 gene encoded-Pgp and MRP1 are members of the ATP binding cassette transporter superfamily. The MDR1 gene encoded-Pgp and MRP1 are members of the ATP binding cassette transporter superfamily Despite their common involvement in MDR, there are clear differences in function and substrate specifity of Pgp and MRP1 [5]. Clarifying the mechanism of action of MRP1 in cell lines ortumors overexpressing MRP1 and the search for inhibitors of drug transport can give new insights in future experiments and therapies
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