State Key Laboratory of Applied Organic Chemistry , Lanzhou University , Lanzhou 730000 , China.
School of Pharmacy , Lanzhou University , Lanzhou 730000 , China.
Mol Pharm. 2018 Aug 6;15(8):3285-3296. doi: 10.1021/acs.molpharmaceut.8b00338. Epub 2018 Jul 5.
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.
旋覆花内酯（XT）是一种存在于苍耳（Xanthium strumarium L.）中的天然倍半萜内酯，目前正在开发为一种有潜力的抗癌药物。尽管 XT 具有有前景的抗癌作用，但它在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）酶是含有硒代半胱氨酸（Sec）残基的末端硒黄素蛋白，是癌症化学治疗剂的有前途的靶标。在这项研究中，XT 抑制了纯化的 TrxR 和细胞中的酶。通过共价对接方法预测了 XT 与 TrxR 蛋白的可能结合模式。机制研究表明，XT 靶向 TrxR 的 Sec 残基并不可逆地抑制酶活性。同时，XT 抑制 TrxR 会促进 HeLa 细胞氧化应激介导的细胞凋亡。重要的是，该酶的敲低使细胞对 XT 处理敏感。因此，靶向 TrxR 揭示了 XT 细胞作用的新分子机制，并为将 XT 开发为抗癌药物提供了思路。
