State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
Free Radic Biol Med. 2019 May 1;135:216-226. doi: 10.1016/j.freeradbiomed.2019.03.014. Epub 2019 Mar 14.
Cancer is considered as one of the highly mortal diseases globally. This is largely due to the lack of efficacious medicines for tumors, and thus development of potent anticancer agents is urgently needed. The thioredoxin (Trx) system is crucial to the survival ability of cells and its expression is up-regulated in many human tumors. Recently, increasing evidence has been established that mammalian thioredoxin reductase (TrxR), a selenocysteine-containing protein and the core component of the thioredoxin system, is a promising therapeutic target. The sesquiterpene lactone compound cynaropicrin (CYN), a major component of Cynara scolymus L., has shown multiple pharmacological functions, especially the anticancer effect, in many experimental models. Most of these functions are concomitant with the production of reactive oxygen species (ROS). Nevertheless, the target of this promising natural anticancer product in redox control has rarely been explored. In this study, we showed that CYN induces apoptosis of Hela cells. Mechanistic studies demonstrated that CYN impinges on the thioredoxin system via inhibition of TrxR, which leads to Trx oxidation and ROS accumulation in HeLa cells. Particularly, the cytotoxicity of CYN is enhanced through the genetic knockdown of TrxR, supporting the pharmacological effect of CYN is relevant to its inhibition of TrxR. Together, our studies reveal an unprecedented mechanism accounting for the anticancer effect of CYN and identify a promising therapeutic agent worthy of further development for cancer therapy.
癌症被认为是全球范围内高致命性疾病之一。这主要是由于缺乏有效的肿瘤药物，因此迫切需要开发有效的抗癌药物。硫氧还蛋白（Trx）系统对细胞的生存能力至关重要，其在许多人类肿瘤中的表达上调。最近，越来越多的证据表明，哺乳动物硫氧还蛋白还原酶（TrxR），一种含硒半胱氨酸的蛋白质，也是硫氧还蛋白系统的核心组成部分，是一个很有前途的治疗靶点。倍半萜内酯化合物莪术呋喃酮（CYN）是大蓟（Cynara scolymus L.）的主要成分，在许多实验模型中表现出多种药理学功能，特别是抗癌作用。这些功能大多与活性氧（ROS）的产生有关。然而，这种有前途的天然抗癌产品在氧化还原控制中的靶点很少被探索。在本研究中，我们表明 CYN 诱导 Hela 细胞凋亡。机制研究表明，CYN 通过抑制 TrxR 作用于硫氧还蛋白系统，导致 Hela 细胞中 Trx 氧化和 ROS 积累。特别是，通过 TrxR 的基因敲低增强了 CYN 的细胞毒性，支持了 CYN 的药理作用与其抑制 TrxR 有关。总之，我们的研究揭示了 CYN 抗癌作用的一个前所未有的机制，并确定了一种有前途的治疗剂，值得进一步开发用于癌症治疗。
