کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8270284 | 1534972 | 2014 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs
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کلمات کلیدی
5-FUeGFPDAPIDCFDAGCLCGCLMAKR1CDMSO - DMSOchromatin immunoprecipitation - ایمن سازی کروماتینDimethyl sulfoxide - دیمتیل سولفواکسیدantioxidant-response element - عنصر پاسخ آنتی اکسیدانی5-fluorouracil - فلوروراسیل-۵، فلوئورواوراسیلARE - هستندenhanced green fluorescent protein - پروتئین فلورسنت سبز افزایش یافته استCHiP - چیپGlutamate–cysteine ligase catalytic subunit - کلوتامین کاتالیستی لیگاز گلوتامات-سیتئین
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: 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](/preview/png/8270284.png)
چکیده انگلیسی
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 not Nrf2â/â 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 of KEAP1. However, forced expression of WT mKeap1 restored the ability of oxaliplatin to activate the transcription factor. Cys151 in 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Free Radical Biology and Medicine - Volume 70, May 2014, Pages 68-77
Journal: Free Radical Biology and Medicine - Volume 70, May 2014, Pages 68-77
نویسندگان
Xiu Jun Wang, Yinyan Li, Lin Luo, Hongyan Wang, Zhexu Chi, Ai Xin, Xin Li, Jiaguo Wu, Xiuwen Tang,