SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer

• DOI: 10.1016/j.phrs.2023.106731
• Publication Date: 2023-03-17T07:33:50Z
• Authors: Yunlong Lu; Xinyu Sheng; Chao Liu; Zhenlin Liang; Xin Wang; Lijuan Liu; Zhenfan Wen; Zhibin Yang; Qianming Du; Wukun Liu
• Keywords: Thioredoxin-Disulfide Reductase; ICD; Estrogen Antagonists; Antineoplastic Agents; Breast Neoplasms; Immunogenic Cell Death; RM1-950; SERD-NHC-Au(I); 3. Good health; Mice; Breast cancer; ER; Cell Line, Tumor; Organometallic Compounds; TrxR; Animals; Humans; Female; Therapeutics. Pharmacology; Gold; Reactive Oxygen Species

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.