Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance.
Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance.
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DOI：
10.1016/j.redox.2012.12.002
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发表时间：
2013
期刊：
影响因子：
11.4
通讯作者：
Keefer, Larry K.
中科院分区：
文献类型：
--
作者：
Maciag, Anna E.;Holland, Ryan J.;Cheng, Y. -S. Robert;Rodriguez, Luis G.;Saavedra, Joseph E.;Anderson, Lucy M.;Keefer, Larry K.
JS-K 是 O2-芳基化二氮烯鎓二醇家族的一种释放一氧化氮 (NO) 的前药，在多种体外和体内癌症模型中均表现出显着的细胞毒性和抗肿瘤特性。目前对 JS-K 代谢作用的研究是为了研究其细胞毒性机制。与模型化学反应一致，细胞中 JS-K 代谢的激活步骤是谷胱甘肽 (GSH) 通过亲核芳香族取代反应对二醇二氮烯鎓进行脱芳基化。所得产物（CEP/NO 阴离子）自发水解，释放出两当量的 NO。 GSH/GSSG 氧化还原对被认为是细胞的主要氧化还原缓冲液，有助于在基础条件下维持还原环境。我们量化了 JS-K 对细胞 GSH 含量的影响，结果表明，由于 JS-K 快速吸收并级联释放 NO 和活性氮，JS-K 显着消耗 GSH。 GSH 的消耗导致细胞环境氧化还原电位的改变，启动 MAPK 应激信号通路，并诱导细胞凋亡。微阵列分析证实了转录水平上的信号基因变化，并揭示了对维持细胞氧化还原稳态以及细胞增殖和存活至关重要的几个基因表达的变化，包括 MYC。用已知的 GSH 前体和亲核还原剂 N-乙酰半胱氨酸预处理细胞可防止导致细胞凋亡的信号事件。这些数据表明，还原型谷胱甘肽库的倍增消耗和细胞内氧化还原平衡的失调是 JS-K 细胞毒性作用机制中重要的初始步骤。 ► JS-K 是一种释放 NO 的前药，具有体外和体内抗癌活性。 ► JS-K 代谢导致细胞谷胱甘肽 (GSH) 芳基化。 ► 培养基中微摩尔水平的 JS-K 会显着耗尽细胞的 GSH 储备。 ► 细胞氧化还原平衡失调是 JS-K 毒性的一个关键因素。
JS-K is a nitric oxide (NO)-releasing prodrug of the O2-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH) via a nucleophilic aromatic substitution reaction. The resulting product (CEP/NO anion) spontaneously hydrolyzes, releasing two equivalents of NO. The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. We have quantified the effects of JS-K on cellular GSH content, and show that JS-K markedly depletes GSH, due to JS-K's rapid uptake and cascading release of NO and reactive nitrogen species. The depletion of GSH results in alterations in the redox potential of the cellular environment, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. Pre-treating cells with the known GSH precursor and nucleophilic reducing agent N-acetylcysteine prevented the signaling events that lead to apoptosis. These data indicate that multiplicative depletion of the reduced glutathione pool and deregulation of intracellular redox balance are important initial steps in the mechanism of JS-K's cytotoxic action. ► JS-K is a NO-releasing prodrug, with anticancer activity in vitro and in vivo. ► JS-K metabolism results in the arylation of cellular glutathione (GSH). ► Micromolar levels of JS-K in media significantly deplete the cellular GSH reserve. ► Deregulation of cells' redox balance is a key contributor to JS-K toxicity.
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影响因子：
7.3
作者：
Maciag, Anna E.;Nandurdikar, Rahul S.;Hong, Sam Y.;Chakrapan, Harinath;Diwan, Bhalchandra;Morris, Nicole L.;Shami, Paul J.;Shiao, Yih-Horng;Anderson, Lucy M.;Keefer, Larry K.;Saavedra, Joseph E.
通讯作者：
Saavedra, Joseph E.
影响因子：
6.4
作者：
SUNDSTROM, C;NILSSON, K
通讯作者：
NILSSON, K
影响因子：
2.9
作者：
GRIFFITH, OW
通讯作者：
GRIFFITH, OW
DOI：
10.1073/pnas.78.12.7492
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
DETHMERS, JK;MEISTER, A
通讯作者：
MEISTER, A
影响因子：
7.4
作者：
Simeone, Ann-Marie;McMurtry, Vanity;Nieves-Alicea, Rene;Saavedra, Joseph E.;Keefer, Larry K.;Johnson, Marcella M.;Tari, Ana M.
通讯作者：
Tari, Ana M.