Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs.
Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs.
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DOI：
10.1016/j.freeradbiomed.2014.02.010
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发表时间：
2014-05
影响因子：
7.4
通讯作者：
X. Wang;Yinyan Li;Lin Luo;Hongyan Wang;Zhexu Chi;Ai Xin;Xin Li;Jia-guo Wu;Xiuwen Tang
中科院分区：
文献类型：
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作者：
X. Wang;Yinyan Li;Lin Luo;Hongyan Wang;Zhexu Chi;Ai Xin;Xin Li;Jia-guo Wu;Xiuwen Tang
奥沙利铂是治疗晚期转移性结直肠癌的重要药物。NF-E2 p45相关因子2 （Nrf2）是一个关键的转录因子，通过其调控区域的抗氧化反应元件（AREs）控制编码细胞保护和解毒酶的基因。在这里，我们报道奥沙利铂是Nrf2信号通路的激活剂，具有re驱动基因的上调和谷胱甘肽的升高。小鼠注射奥沙利铂可增强野生型（WT）小鼠小肠和大肠谷胱甘肽转移酶和抗氧化酶的表达，但对tnrf2−/−小鼠没有作用，表明奥沙利铂在体内激活Nrf2。奥沙利铂未能增加非小细胞肺癌A549细胞中Nrf2的积累，A549细胞中存在功能失调的keap1体细胞突变。然而，强行表达WT mKeap1恢复了奥沙利铂激活转录因子的能力。Keap1中的cys151是奥沙利铂刺激应答所必需的。此外，奥沙利铂的代谢物二氯（1,2-二氨基环己烷）铂被发现在激活are基因电池方面具有与其母体药物相同的效果，而另一种代谢物草酸盐则无效。此外，另外两种铂衍生物顺铂和卡铂对Keap1/Nrf2系统没有影响。此外，奥沙利铂激活Nrf2降低了结肠癌细胞对治疗药物的敏感性。相反，Nrf2 siRNA敲低Nrf2可减少奥沙利铂诱导的化疗耐药。我们的研究表明奥沙利铂通过Nrf2对抗癌药物的细胞毒性发挥保护作用，提示Nrf2在奥沙利铂为基础的化疗中发挥重要作用。
Oxaliplatin is an important drug in the treatment of advanced metastatic colorectal cancer. NF-E2 p45-related factor 2 (Nrf2) is a key transcription factor that controls genes encoding cytoprotective and detoxifying enzymes through antioxidant-response elements (AREs) in their regulatory regions. Here, we report that oxaliplatin is an activator of the Nrf2 signaling pathway, with upregulation of ARE-driven genes and glutathione elevation. An injection of oxaliplatin into mice enhanced the expression of glutathione transferases and antioxidant enzymes in the small and large intestines of wild-type (WT) mice but notNrf2−/−mice, indicating that oxaliplatin activates Nrf2 in vivo. Oxaliplatin failed to increase Nrf2 accumulation in non-small-cell lung cancer A549 cells, which harbor a dysfunctional somatic mutation ofKEAP1. However, forced expression of WT mKeap1 restored the ability of oxaliplatin to activate the transcription factor. Cys151in Keap1 was required for the response stimulated by oxaliplatin. In addition, dichloro(1,2-diaminocyclohexane) platinum, a metabolite of oxaliplatin, was found to have the same effect in activating the ARE-gene battery as its parent drug, whereas another metabolite, oxalate, was ineffective. Moreover, two other platinum derivatives, cisplatin and carboplatin, had no effect on the Keap1/Nrf2 system. Furthermore, activation of Nrf2 by oxaliplatin reduced the sensitivity of colon cancer cells to therapeutic drugs. Conversely, knockdown of Nrf2 by Nrf2 siRNA reduced oxaliplatin-induced chemoresistance. Our study showed that oxaliplatin exerts protection against the cytotoxicity of anticancer drugs via Nrf2, indicating an important role of Nrf2 in oxaliplatin-based chemotherapy.