Drug resistance associates with activation of Nrf2 in MCF‐7/DOX cells, and wogonin reverses it by down‐regulating Nrf2‐mediated cellular defense response
Drug resistance associates with activation of Nrf2 in MCF‐7/DOX cells, and wogonin reverses it by down‐regulating Nrf2‐mediated cellular defense response
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DOI：
10.1002/mc.21921
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发表时间：
2013-10
影响因子：
4.6
通讯作者：
Y. Zhong;Fengyi Zhang;Zhong-ying Sun;W. Zhou;Zhi-yu Li;Q. You;Q. Guo;Rong Hu
中科院分区：
文献类型：
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作者：
Y. Zhong;Fengyi Zhang;Zhong-ying Sun;W. Zhou;Zhi-yu Li;Q. You;Q. Guo;Rong Hu
获得性多柔比星耐药是乳腺癌患者治疗中的一个严重问题。在这项研究中，我们研究了核因子红细胞2相关因子2（Nrf 2）是否与DOX耐药MCF-7（MCF-7/DOX）细胞的耐药性相关，以及从黄芩根中分离的黄酮类化合物汉黄芩素是否可以逆转MCF-7/DOX细胞的耐药性。我们发现MCF-7/DOX细胞中Nrf 2及其靶蛋白血红素加氧酶-1（HO-1）、NADP（H）：醌氧化还原酶（NQO）的内源性表达高于MCF-7细胞。叔丁基对苯二酚处理增加了Nrf 2、HO-1和NQO-1的表达，并增强了MCF-7细胞对DOX的抗性。类似地，MCF-7/DOX细胞中的细胞内Nrf 2蛋白水平显著降低，并且DOX抗性被Nrf 2 siRNA部分逆转。汉黄芩素下调MCF-7/DOX细胞中Nrf 2依赖性反应并部分逆转DOX抗性。这些结果表明，Nrf 2的活化与MCF-7/DOX细胞的耐药性相关。汉黄芩素逆转耐药的机制可能是通过抑制Nrf 2信号通路，提示利用Nrf 2抑制剂提高化疗药物疗效的可行性。© 2012 Wiley Periodicals，Inc.
Acquired resistance to doxorubicin (DOX) is a serious therapeutic problem in breast cancer patients. In this study, we investigated whether nuclear factor erythroid 2‐related factor 2 (Nrf2) was associated with drug resistant in DOX resistant MCF‐7 (MCF‐7/DOX) cells, and if wogonin, a flavonoid isolated from the root of Scutellaria baicalensis Georgi, could reverse drug resistance in MCF‐7/DOX cells. We found that the endogenous expression of Nrf2 as well as its target proteins heme oxygenase‐1 (HO‐1), NADP(H):quinone oxidoreductase (NQO) in MCF‐7/DOX cells was higher than that in MCF‐7 cells. Tert‐butylhydroquinone treatment increased the expression Nrf2, HO‐1, and NQO‐1, and enhanced resistance of MCF‐7 cells to DOX. Similarly, intracellular Nrf2 protein level was significantly decreased in MCF‐7/DOX cells and DOX resistance was partially reversed by Nrf2 siRNA. Wogonin downregulated the Nrf2‐dependent response and partly reversed DOX resistance in MCF‐7/DOX cells. These results suggested that activation of Nrf2 was associated with drug resistance in MCF‐7/DOX cells. Wogonin reversed drug resistance and its reversal mechanism might be due to the suppression of Nrf2 signaling pathway, indicating the feasibility of using Nrf2 inhibitors to increase efficacy of chemotherapeutic drugs. © 2012 Wiley Periodicals, Inc.