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Xanthatin Promotes Apoptosis via Inhibiting Thioredoxin Reductase and Eliciting Oxidative Stress
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-06-25 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00338
Ruijuan Liu 1, 2 , Danfeng Shi 3 , Junmin Zhang 2 , Xinming Li 1, 3 , Xiao Han 1, 3 , Xiaojun Yao 3 , Jianguo Fang 1, 3
Affiliation  

Xanthatin (XT), a naturally occurring sesquiterpene lactone presented in cocklebur (Xanthium strumarium L.), is under development as a potential anticancer agent. Despite the promising anticancer effect of XT, the molecular mechanism underlying its cellular action has not been well elucidated. The mammalian thioredoxin reductase (TrxR) enzymes, the essential seleno-flavoproteins containing a penultimate selenocysteine (Sec) residue at the C-terminus, represent a promising target for cancer chemotherapeutic agents. In this study, XT inhibits both the purified TrxR and the enzyme in cells. The possible binding mode of XT with the TrxR protein is predicted by the covalent docking method. Mechanism studies reveal that XT targets the Sec residue of TrxR and inhibits the enzyme activity irreversibly. Simultaneously, the inhibition of TrxR by XT promotes the oxidative stress-mediated apoptosis of HeLa cells. Importantly, the knockdown of the enzyme sensitizes the cells to XT treatment. Targeting TrxR thus discloses a novel molecular mechanism in accounting for the cellular action of XT and provides insights into the development of XT as an anticancer agent.

中文翻译:

Xanthatin通过抑制硫氧还蛋白还原酶和减轻氧化应激来促进细胞凋亡

Xanthatin(XT),一种存在于鸟蛤中的天然倍半萜内酯(Xanthium strumarium L.),正在开发作为潜在的抗癌药。尽管XT具有令人鼓舞的抗癌作用,但其细胞作用的分子机制尚未得到很好的阐明。哺乳动物硫氧还蛋白还原酶(TrxR)酶是在C末端包含倒数第二个硒代半胱氨酸(Sec)残基的必需硒代黄素蛋白,是癌症化疗药物的有希望的靶标。在这项研究中,XT抑制细胞中纯化的TrxR和酶。XT与TrxR蛋白的可能结合方式是通过共价对接方法预测的。机理研究表明,XT靶向TrxR的Sec残基并不可逆地抑制酶的活性。同时,XT对TrxR的抑制作用促进了氧化应激介导的HeLa细胞凋亡。重要的,酶的敲低使细胞对XT处理敏感。因此,靶向TrxR揭示了XT的细胞作用的新型分子机制,并为XT作为抗癌药的发展提供了见识。
更新日期:2018-06-25
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