Zheng Ya-Long, Ji Yuan, Li Yan, Yan Shuai, Ren Xiao-Rong, Tang Wei, Dai Fang, Zhou Bo
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., 730000, Lanzhou, Gansu, China; Medicine College of Pingdingshan University, 467000, Pingdingshan, Henan, China.
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., 730000, Lanzhou, Gansu, China.
Free Radic Biol Med. 2025 Feb 1;227:27-41. doi: 10.1016/j.freeradbiomed.2024.11.049. Epub 2024 Nov 27.
The development of Cu(II) ionophores for targeted disruption of aberrant redox homeostasis in cancer cells has been considered an appealing strategy in the field of anticancer research. This study presents the first identification of tanshinone I (Ts1), a natural o-quinone, as a Cu(II) ionophore. Structure-activity relationship studies on tanshinones and mechanistic investigations reveal that the presence of Cu(II) effectively promotes the tautomerization of Ts1 from its diketo to keto-enol forms, thereby facilitating its sequential proton-loss Cu(II) chelation, and enabling it to function as a Cu(II) ionophore due to its structural features including the presence of an o-quinone moiety, a benzyl hydrogen, and a large conjugated system. The unique property allows Ts1 to preferentially induce copper accumulation in human hepatoma HepG2 cells over human umbilical vein endothelial cells, by releasing copper driven by reduced glutathione (GSH). This copper accumulation leads to a reduction in the GSH-to-oxidized glutathione ratio and the generation of reactive oxygen species, ultimately triggering apoptosis of HepG2 cells. The findings not only provide support for o-quinones as innovative types of anticancer Cu(II) ionophores, but also shed light on the previously unrecognized role of Ts1 as a potent Cu(II) ionophore for eradicating cancer cells by selectively disrupting their redox regulation programs, resembling a "Trojan horse".
开发用于靶向破坏癌细胞中异常氧化还原稳态的铜（II）离子载体，已被认为是抗癌研究领域中一种有吸引力的策略。本研究首次鉴定出丹参酮I（Ts1），一种天然邻醌，作为铜（II）离子载体。对丹参酮的构效关系研究和机理研究表明，铜（II）的存在有效地促进了Ts1从其二酮形式到酮 - 烯醇形式的互变异构，从而促进其顺序质子损失铜（II）螯合，并由于其结构特征（包括邻醌部分、苄基氢和大共轭体系的存在）使其能够作为铜（II）离子载体发挥作用。这种独特性质使Ts1能够通过还原型谷胱甘肽（GSH）驱动释放铜，从而优先诱导人肝癌HepG2细胞而非人脐静脉内皮细胞中的铜积累。这种铜积累导致谷胱甘肽与氧化型谷胱甘肽比例降低和活性氧的产生，最终引发HepG2细胞凋亡。这些发现不仅为邻醌作为新型抗癌铜（II）离子载体提供了支持，也揭示了Ts1作为一种有效的铜（II）离子载体，通过选择性破坏癌细胞的氧化还原调节程序来根除癌细胞的先前未被认识的作用，类似于“特洛伊木马”。
