School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):790-801. doi: 10.1080/14756366.2021.1899169.
Isolation and identification of natural products from plants is an essential approach for discovering drug candidates. Herein we report the characterization of three sesquiterpene lactones from a new genus , e.g. onopordopicrin (ONP), C, and C, and evaluation of their pharmacological functions in interfering cellular redox signaling. Compared to C and C, ONP shows the most potency in killing cancer cells. Further experiments demonstrate that ONP robustly inhibits thioredoxin reductase (TrxR), which leads to perturbation of cellular redox homeostasis with the favor of oxidative stress. Knockdown of the TrxR sensitizes cells to the ONP treatment while overexpression of the enzyme reduces the potency of ONP, underpinning the correlation of TrxR inhibition to the cytotoxicity of ONP. The discovery of ONP expands the library of the natural TrxR inhibitors, and the disclosure of the action mechanism of ONP provides a foundation for the further development of ONP as an anticancer agent.
从植物中分离和鉴定天然产物是发现药物候选物的一种重要方法。在此，我们报告了从一个新属中分离得到的三种倍半萜内酯的特征，例如，ONP（onopordopicrin）、C 和 C，并评估了它们在干扰细胞氧化还原信号中的药理学功能。与 C 和 C 相比，ONP 在杀死癌细胞方面表现出最强的效力。进一步的实验表明，ONP 能强烈抑制硫氧还蛋白还原酶（TrxR），导致细胞氧化还原平衡紊乱，有利于氧化应激。TrxR 的敲低使细胞对 ONP 处理敏感，而酶的过表达降低了 ONP 的效力，这表明 TrxR 抑制与 ONP 的细胞毒性相关。ONP 的发现扩展了天然 TrxR 抑制剂库，ONP 作用机制的揭示为进一步将 ONP 开发为抗癌药物提供了基础。
