Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1.
Distinct responses of compartmentalized glutathione redox potentials to pharmacologic quinones targeting NQO1.
复制标题
区室化谷胱甘肽氧化还原电位对靶向 NQO1 的药理学醌的独特反应。
DOI：
10.1016/j.bbrc.2016.12.082
复制
发表时间：
2017
影响因子：
3.1
通讯作者：
Gaskins,HRex
中科院分区：
文献类型：
--
作者：
Kolossov,VladimirL;Ponnuraj,Nagendraprabhu;Beaudoin,JessicaN;Leslie,MatthewT;Kenis,PaulJ;Gaskins,HRex
Deoxynyboquinone (DNQ) 是一种有效的新型醌基抗肿瘤剂，通过过量产生 ROS，选择性杀死胞质 NAD(P)H:醌氧化还原酶-1 (NQO1) 过表达的实体癌。基因编码的氧化还原敏感探针用于监测细胞器内谷胱甘肽氧化还原电位（EGSH），作为化疗后细胞氧化应激的直接指标。在与或不与双香豆素和 ES936（强效 NQO1 抑制剂）一起孵育的人肺 A549 和胰腺 MIA-PaCa-2 腺癌细胞中，监测 β-拉帕酮 (β-lap) 和 DNQ 诱导的时空氧化还原反应。观察到细胞质和线粒体基质中 EGSH 对 DNQ 和 β-lap 的立即氧化反应。 NQO1 抑制可完全阻止 DNQ 诱导的胞质氧化，而与 MIA-PaCa-2 细胞相比，A549 中的线粒体氧化不依赖于 NQO1。然而，在 β-lap 的药理学浓度下，两种基于醌的底物都直接氧化氧化还原探针，这可能是与细胞硫醇发生脱靶反应的迹象。总之，这些数据提供了新的证据，证明 DNQ 直接且敏锐的 NQO1 底物特异性是其药理效力的基础，而 β-lap 在其有效剂量下会引发脱靶反应。
Deoxynyboquinone (DNQ), a potent novel quinone-based antineoplastic agent, selectively kills solid cancers with overexpressed cytosolic NAD(P)H:quinone oxidoreductase-1 (NQO1) via excessive ROS production. A genetically encoded redox-sensitive probe was used to monitor intraorganellar glutathione redox potentials (EGSH) as a direct indicator of cellular oxidative stress following chemotherapeutic administration. Beta-lapachone (β-lap) and DNQ-induced spatiotemporal redox responses were monitored in human lung A549 and pancreatic MIA-PaCa-2 adenocarcinoma cells incubated with or without dicumarol and ES936, potent NQO1 inhibitors. Immediate oxidation of EGSHin both the cytosol and mitochondrial matrix was observed in response to DNQ and β-lap. The DNQ-induced cytosolic oxidation was fully prevented with NQO1 inhibition, whereas mitochondrial oxidation in A549 was NQO1-independent in contrast to MIA-PaCa-2 cells. However, at pharmacologic concentrations of β-lap both quinone-based substrates directly oxidized the redox probe, a possible sign of off-target reactivity with cellular thiols. Together, these data provide new evidence that DNQ's direct and discerning NQO1 substrate specificity underlies its pharmacologic potency, while β-lap elicits off-target responses at its effective doses.