Quinone-induced activation of Keap1/Nrf2 signaling by aspirin prodrugs masquerading as nitric oxide.
Quinone-induced activation of Keap1/Nrf2 signaling by aspirin prodrugs masquerading as nitric oxide.
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DOI：
10.1021/tx3003609
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发表时间：
2012-12-17
影响因子：
4.1
通讯作者：
Thatcher GR
中科院分区：
文献类型：
--
作者：
Dunlap T;Piyankarage SC;Wijewickrama GT;Abdul-Hay S;Vanni M;Litosh V;Luo J;Thatcher GR
NO-供体混合阿司匹林前药（NO-ASA）的有前途的治疗潜力，包括诱导化学预防机制，并已在近100篇出版物中报道。一个例子，NCX-4040（pNO-ASA），通过酯酶生物活化为醌甲基化物（QM）亲电体。在细胞培养物中，不能释放NO的pNO-ASA和QM供体X-ASA前药迅速耗尽细胞内GSH并引起DNA损伤;然而，Nrf 2信号传导的诱导引起细胞防御机制，包括NAD（P）H：醌氧化还原酶-1（NQO 1）和谷氨酸-半胱氨酸连接酶（GCL）的上调。在HepG 2细胞中，“NO特异性”4，5-二氨基荧光素报告基因DAF-DA对NO-ASA和X-ASA有反应，QM诱导的氧化应激伪装成NO。LC-MS/MS分析表明，包括谷胱甘肽-S-转移酶-P1（GST-P1）和Kelch样ECH相关蛋白1（Keap 1）在内的蛋白质的Cys残基有效烷基化。Keap 1 Cys残基的烷基化与Nrf 2易位到细胞核，Nrf 2的核易位，抗氧化反应元件（ARE）的激活和细胞保护靶基因的上调相关的证据。至少在细胞培养中，pNO-ASA作为QM供体，通过细胞酯酶活性生物活化，释放水杨酸盐、NO3−和亲电子QM。最后，合成了两种新的阿司匹林前药，它们都是ARE的有效激活剂，设计为在生物激活时仅释放QM和水杨酸酯。目前对通过Nrf 2信号作用的亲电药物的兴趣表明，QM-供体杂交药物可以被设计为药物发现中的信息化学探针。
The promising therapeutic potential of the NO-donating hybrid aspirin prodrugs (NO-ASA), includes induction of chemopreventive mechanisms, and has been reported in almost 100 publications. One example, NCX-4040 (pNO-ASA), is bioactivated by esterase to a quinone methide (QM) electrophile. In cell cultures, pNO-ASA and QM-donating X-ASA prodrugs that cannot release NO rapidly depleted intracellular GSH and caused DNA damage; however, induction of Nrf2 signaling elicited cellular defense mechanisms including upregulation of NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase (GCL). In HepG2 cells, the “NO-specific” 4,5-diaminofluorescein reporter, DAF-DA, responded to NO-ASA and X-ASA, with QM-induced oxidative stress masquerading as NO. LC-MS/MS analysis demonstrated efficient alkylation of Cys residues of proteins including glutathione-S-transferase-P1 (GST-P1) and Kelch-like ECH-associated protein 1 (Keap1). Evidence was obtained for alkylation of Keap1 Cys residues associated with Nrf2 translocation to the nucleus, nuclear translocation of Nrf2, activation of antioxidant response element (ARE), and upregulation of cytoprotective target genes. At least in cell culture, pNO-ASA acts as a QM-donor, bioactivated by cellular esterase activity to release salicylates, NO3−, and an electrophilic QM. Finally, two novel aspirin prodrugs were synthesized, both potent activators of ARE, designed to release only the QM and salicylates on bioactivation. Current interest in electrophilic drugs acting via Nrf2 signaling suggests that QM-donating hybrid drugs can be designed as informative chemical probes in drug discovery.
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DOI：
10.1073/pnas.0511250103
发表时间：
2006-03-07
影响因子：
11.1
作者：
Bratasz, A;Weir, NM;Kuppusamy, P
通讯作者：
Kuppusamy, P
影响因子：
4.1
作者：
Dunlap, Tareisha;Chandrasena, R. Esala P.;Thatcher, Gregory R. J.
通讯作者：
Thatcher, Gregory R. J.
DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
影响因子：
4.1
作者：
Chandrasena, R. Esala P.;Edirisinghe, Praneeth D.;Thatcher, Gregory R. J.
通讯作者：
Thatcher, Gregory R. J.
影响因子：
2.9
作者：
Chang, MS;Shin, YG;Bolton, JL
通讯作者：
Bolton, JL