약학회지 (YAKHAK HOEJI)

  • 제52권1호
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  • Pages.67-72
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  • 2008
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  • 0377-9556(pISSN)
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  • 2383-9457(eISSN)
대한약학회 (The Pharmaceutical Society of Korea)
권호 표지

Doxorubicin 매개 세포독성에 대한 Nrf2 경로의 역할

Sensitization to Doxorubicin by Inhibition of the Nrf2-Antioxidant System

  • 발행 : 2008.02.29
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초록

The use of doxorubicin, which is one of the most effective anticancer agents, is often limited by occurrence of acquired resistance in tumor cells. GSH has been shown to be involved in the development of this drug resistance. Transcription factor Nrf2 governs the expression of GSH synthesizing glutamylcysteine ligase (GCL), as well as multiple phase 2 detoxifying enzymes. Here we show that Nrf2 is one of factors determining doxorubicin sensitivity. Nrf2-deficient fibroblasts (murine embryonic fibroblasts, MEF) were more susceptible to doxorubicin mediated cell death than wild-type cells. Doxorubicin treatment elevated levels of Nrf2-regulated genes including NAD(P)H: quinone oxidoreductase (Nqo1) and GCL in wild-type fibroblasts, while no induction was observed in Nrf2-deficient cells. Doxorubicin resistance in human ovarian SK-OV cells was reversed by treatment with L-buthionine-sulfoxamine (BSO), which is depleting intracellular GSH. Finally, transfection of SK-OV cells with Nrf2 siRNA resulted in exacerbated cytotoxicity following doxorubicin treatment compared to scrambled RNA control. These results indicate that the Nrf2 pathway, which plays a protective role in normal cells, can be a potential target to control cancer cell resistance to anticancer agents.

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