硫氧还蛋白还原酶
雌激素受体
癌症研究
乳腺癌
化学
癌症
癌细胞
硫氧还蛋白
酶
医学
生物化学
内科学
作者
Yunlong Lu,Xinyu Sheng,Chao Liu,Zhenlin Liang,Xin Wang,Lijuan Liu,Zhenfan Wen,Zhibin Ye,Qianming Du,Wukun Liu
标识
DOI:10.1016/j.phrs.2023.106731
摘要
The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate——G1T48 (NCT03455270), with a TrxR inhibitor——N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model.
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