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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide
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Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide

机译：靶向硫氧还蛋白还原酶是三氧化二砷治疗癌症的基础

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Arsenic trioxide (ATO) is an effective cancer therapeutic drug for acute promyelocytic leukemia and has potential anticancer activity against a wide range of solid tumors. ATO exerts its effect mainly through elevated oxidative stress, but the exact molecular mechanism remains elusive. The thioredoxin (Trx) system comprising NADPH, thioredoxin reductase (TrxR), and Trx and the glutathione (GSH) system composed of NADPH, glutathione reductase, and GSH supported by glutaredoxin are the two electron donor systems that control cellular proliferation, viability, and apoptosis. Recently, the selenocysteine-dependent TrxR enzyme has emerged as an important molecular target for anticancer drug development. Here, we have discovered that ATO irreversibly inhibits mammalian TrxR with an IC_(50) of 0.25 μM. Both the N-terminal redox-active dithiol and the C-terminal selenothiol-active site of reduced TrxR may participate in the reaction with ATO. The inhibition of MCF-7 cell growth by ATO was correlated with irreversible inactivation of TrxR, which subsequently led to Trx oxidation. Furthermore, the inhibition of TrxR by ATO was attenuated by GSH, and GSH depletion by buthionine sulfoximine enhanced ATO-induced cell death. These results strongly suggest that the ATO anticancer activity is by means of a Trx system-mediated apoptosis. Blocking cancer cell DNA replication and repair and induction of oxidative stress by the inhibition of both Trx and GSH systems are suggested as cancer chemotherapeutic strategies.
机译：三氧化二砷（ATO）是用于急性早幼粒细胞白血病的有效癌症治疗药物，对多种实体瘤具有潜在的抗癌活性。 ATO主要通过增加氧化应激发挥其作用，但确切的分子机制仍然难以捉摸。包含NADPH，硫氧还蛋白还原酶（TrxR）和Trx的硫氧还蛋白（Trx）系统以及由谷胱甘肽支持的NADPH，谷胱甘肽还原酶和GSH组成的谷胱甘肽（GSH）系统是控制细胞增殖，生存力和活性的两个电子供体系统。细胞凋亡。最近，依赖于硒代半胱氨酸的TrxR酶已成为抗癌药物开发的重要分子靶标。在这里，我们发现ATO不可逆地抑制哺乳动物TrxR，IC_（50）为0.25μM。 TrxR还原的N端氧化还原活性二硫醇和C端硒醇活性位点均可参与与ATO的反应。 ATO对MCF-7细胞生长的抑制作用与TrxR的不可逆失活有关，后者随后导致Trx氧化。此外，GSH减弱了ATO对TrxR的抑制作用，丁硫氨酸磺胺嘧啶对GSH的耗竭增强了ATO诱导的细胞死亡。这些结果强烈表明ATO抗癌活性是通过Trx系统介导的细胞凋亡。建议通过抑制Trx和GSH系统来阻止癌细胞DNA复制和修复以及诱导氧化应激，这是癌症的化学治疗策略。

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