Securinine disturbs redox homeostasis and elicits oxidative stress-mediated apoptosis via targeting thioredoxin reductase
Securinine disturbs redox homeostasis and elicits oxidative stress-mediated apoptosis via targeting thioredoxin reductase
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叶秋碱通过靶向硫氧还蛋白还原酶扰乱氧化还原稳态并引发氧化应激介导的细胞凋亡
DOI：
10.1016/j.bbadis.2016.10.019
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Fang Jianguo
中科院分区：
文献类型：
--
作者：
Zhang Junmin;Yao Juan;Peng Shoujiao;Li Xinming;Fang Jianguo
硫氧还蛋白还原酶（TrxR）和硫氧还蛋白（Trx）是硫氧还蛋白系统的两个主要组成部分，在细胞氧化还原信号转导中起着重要的调节作用。哺乳动物的TrxR是一种重要的硒黄素酶，其C-末端具有保守的倒数第二个硒代半胱氨酸（Sec）残基，并且作为有希望的抗癌药物靶点吸引了相当大的兴趣。一叶秋碱（Securinine，SCR）是从中草药一叶秋中提取的一种主要生物碱内酯类化合物，在神经系统疾病的治疗中取得了临床成功。近年来，越来越多的证据表明，SCR对多种肿瘤细胞具有潜在的细胞毒性作用，使这种古老的中枢神经系统药物成为一种潜在的肿瘤治疗药物。然而，SCR的抗癌活性的机制还没有很好的定义。我们在这里报道了SCR抑制纯化的TrxR和完整细胞中的酶。SCR可导致活性氧（ROS）的积累、氧化型谷胱甘肽和Trx的升高，破坏氧化还原平衡，最终导致氧化应激介导的HeLa细胞凋亡。重要的是，TrxR的药理学抑制或敲低使细胞对SCR处理敏感，从而支持通过SCR靶向TrxR的生理学意义。我们的发现揭示了一种新的机制，潜在的SCR的抗癌活性，并提供了基础数据，为进一步开发SCR作为癌症化疗药物。
Thioredoxin reductase (TrxR) and thioredoxin (Trx) are two major components of the thioredoxin system, which plays essential roles in regulating cellular redox signaling. Mammalian TrxRs are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted considerable interests as promising targets for anticancer drugs. Securinine (SCR), a major active alkaloid lactone from the Chinese herbal medicineSecurinega suffruticosa, has been established clinical success in treatment of neurological disorders. Recently, increasing evidence demonstrates that SCR has potential cytotoxicity to various types of tumor cells, which enables this old central nervous system drug as a potential cancer therapeutic agent. However, the mechanism underlying the anticancer activity of SCR is not well defined. We reported here that SCR inhibits both the purified TrxR and the enzyme in intact cells. SCR elicits accumulation of reactive oxygen species (ROS), elevation of oxidized glutathione and Trx, disturbs redox homeostasis, and eventually leads to oxidative stress-mediated HeLa cell apoptosis. Importantly, pharmacological inhibition or knockdown of TrxR sensitizes the cells to SCR treatment, underpinning the physiological significance of targeting TrxR by SCR. Our discovery discloses a novel mechanism underlying the anticancer activity of SCR and provides basic data for further development of SCR as a cancer chemotherapeutic drug.