期刊
PHARMACOLOGICAL RESEARCH
卷 190, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2023.106731
关键词
ER; SERD-NHC-Au(I); TrxR; ICD; Breast cancer
The development of selective estrogen receptor degraders (SERDs) has provided new ideas for the clinical treatment of ER-positive advanced breast cancer. This study combines a clinical SERD candidate-G1T48 with a TrxR inhibitor-NHC-Au(I) to form dual targeting complexes, which showed significant antiproliferative effects by degrading ER and inhibiting TrxR activity. The complexes also induced immunogenic cell death (ICD) through ROS, providing evidence for the role of the ER/TrxR-ROS-ICD axis in ER-positive breast cancer.
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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