Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: Implication to cancer cell resistance
Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: Implication to cancer cell resistance
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DOI：
10.1016/j.canlet.2007.10.022
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发表时间：
2008-02-18
期刊：
影响因子：
9.7
通讯作者：
Kwak, Mi-Kyoung
中科院分区：
文献类型：
--
作者：
Cho, Jeong-Min;Manandhar, Sarala;Kwak, Mi-Kyoung
烷基化细胞毒药物顺铂的治疗常常因耐药发生率高而受到限制。在本研究中，研究了转录因子 Nrf2 在顺铂细胞毒性测定中的潜在参与。与野生型细胞相比，Nrf2 缺陷型小鼠胚胎成纤维细胞对顺铂治疗的反应显示出细胞死亡、细胞毒性和凋亡增加。顺铂耐药的人卵巢癌 SK-OV 细胞保留的 GSH 水平比小鼠成纤维细胞高 25 倍，可以通过抑制 Nrf2 来致敏。与乱序 RNA 对照相比，用 Nrf2 siRNA 转染 SK-OV 细胞会导致严重程度的 GSH 消耗，并在顺铂处理后加剧细胞毒性。总之，我们提出在正常细胞中起保护作用的Nrf2通路可以成为控制癌细胞对氧化剂、细胞毒性化学物质和辐射的抵抗力的潜在靶点。 (C) 2007 Elsevier Ireland Ltd. 保留所有权利。
The treatment of alkylating cytotoxic drug cisplatin is often limited by high incidence rate of resistance. In the present study, the potential involvement of the transcription factor Nrf2 in determination of cisplatin cytotoxicity has been investigated. Nrf2-deficient murine embryonic fibroblasts showed increased cell death, cytotoxicity, and apoptosis in response to cisplatin treatment compared to wild-type cells. Cisplatin-resistant human ovarian cancer SK-OV cells, which are retaining 25-fold higher levels of GSH than murine fibroblasts, could be sensitized by inhibition of Nrf2. Transfection with Nrf2 siRNA into SK-OV cells resulted in severe degree of GSH depletion and exacerbated cytotoxicity following cisplatin treatment compared to scrambled RNA control. In conclusion, we propose that the Nrf2 pathway, which plays a protective role in normal cells, can be a potential target to control cancer cell resistance to oxidants, cytotoxic chemicals, and radiation. (C) 2007 Elsevier Ireland Ltd. All rights reserved.