Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin.
Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin.
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DOI：
10.1016/j.redox.2021.102184
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发表时间：
2021-11-11
期刊：
影响因子：
11.4
通讯作者：
Arnér ESJ
中科院分区：
文献类型：
--
作者：
Sabatier P;Beusch CM;Gencheva R;Cheng Q;Zubarev R;Arnér ESJ
靶向细胞抗氧化系统的抗癌药物最近引起了人们的广泛关注。金诺芬（AF）目前在几项临床试验中被评估为靶向硒蛋白硫氧还蛋白还原酶TXNRD 1和TXNRD 2的细胞溶质和线粒体形式的抗癌剂。最近，已经开发了两种新型TXNRD 1抑制剂（TRi-1和TRi-2），其显示出与AF相当的抗癌功效，但具有较低的线粒体毒性。然而，这些药物的细胞作用机制尚未得到彻底研究。在这里，我们使用了几种蛋白质组学方法来确定AF、TRi-1和TRi-2在IC 50浓度下对小鼠B16黑色素瘤和LLC肺腺癌细胞的作用，因为这些通常用于临床前小鼠模型评估抗癌药物。结果表明，TRi-1和TRi-2是比AF更特异的TXNRD 1抑制剂，并揭示了对细胞蛋白质组的额外AF特异性作用。有趣的是，AF引发了比其他两种化合物更强的Nrf 2驱动的抗氧化反应。此外，AF还影响了其他几种蛋白质，包括GSK 3A、GSK 3B、MCMBP和EEFSEC，这意味着对糖原代谢、细胞分化、炎症通路、DNA复制和硒蛋白合成过程产生了其他影响。我们的蛋白质组学数据为研究人员提供了一个资源，他们对与氧化应激相关的蛋白质组变化的多维分析感兴趣，特别是TXNRD 1抑制剂和AF蛋白靶点的影响。金诺芬是一种硫氧还蛋白还原酶抑制剂，目前正在进行抗癌临床试验。TRi-1和TRi-2是最近开发的具有抗癌作用的硫氧还蛋白还原酶替代抑制剂。综合蛋白质组学揭示了金诺芬除了硫氧还蛋白还原酶之外的其他靶点。TRi-2是比金诺芬更特异的硫氧还蛋白还原酶抑制剂，但也靶向醛酮还原酶。TRi-1是这三种化合物中最特异的硫氧还蛋白还原酶抑制剂。
Anticancer drugs that target cellular antioxidant systems have recently attracted much attention. Auranofin (AF) is currently evaluated in several clinical trials as an anticancer agent that targets the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase, TXNRD1 and TXNRD2. Recently, two novel TXNRD1 inhibitors (TRi-1 and TRi-2) have been developed that showed anticancer efficacy comparable to AF, but with lower mitochondrial toxicity. However, the cellular action mechanisms of these drugs have not yet been thoroughly studied. Here we used several proteomics approaches to determine the effects of AF, TRi-1 and TRi-2 when used at IC50 concentrations with the mouse B16 melanoma and LLC lung adenocarcinoma cells, as these are often used for preclinical mouse models in evaluation of anticancer drugs. The results demonstrate that TRi-1 and TRi-2 are more specific TXNRD1 inhibitors than AF and reveal additional AF-specific effects on the cellular proteome. Interestingly, AF triggered stronger Nrf2-driven antioxidant responses than the other two compounds. Furthermore, AF affected several additional proteins, including GSK3A, GSK3B, MCMBP and EEFSEC, implicating additional effects on glycogen metabolism, cellular differentiation, inflammatory pathways, DNA replication and selenoprotein synthesis processes. Our proteomics data provide a resource for researchers interested in the multidimensional analysis of proteome changes associated with oxidative stress in general, and the effects of TXNRD1 inhibitors and AF protein targets in particular. Auranofin is an inhibitor of thioredoxin reductase currently in clinical trials against cancer. TRi-1 and TRi-2 are recently developed alternative inhibitors of thioredoxin reductase with anticancer effects. Comprehensive proteomics reveal additional targets of Auranofin beyond thioredoxin reductase. TRi-2 is a more specific thioredoxin reductase inhibitor than Auranofin but also targets aldo-keto reductases. TRi-1 is the most specific thioredoxin reductase inhibitor of these three compounds.
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影响因子：
3.7
作者：
Anestål K;Prast-Nielsen S;Cenas N;Arnér ES
通讯作者：
Arnér ES
影响因子：
16.6
作者：
Eriksson, Sofi;Prigge, Justin R.;Talago, Emily A.;Arner, Elias S. J.;Schmidt, Edward E.
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通讯作者：
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作者：
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通讯作者：
Zubarev, Roman A.