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

Pharmacol Res. 2023 Apr:190:106731. doi: 10.1016/j.phrs.2023.106731. Epub 2023 Mar 17.

Abstract

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.

Keywords: Breast cancer; ER; ICD; SERD-NHC-Au(I); TrxR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / metabolism
  • Cell Line, Tumor
  • Estrogen Antagonists / therapeutic use
  • Female
  • Gold / chemistry
  • Humans
  • Immunogenic Cell Death
  • Mice
  • Organometallic Compounds / pharmacology
  • Reactive Oxygen Species / metabolism
  • Thioredoxin-Disulfide Reductase / metabolism

Substances

  • Antineoplastic Agents
  • Estrogen Antagonists
  • Reactive Oxygen Species
  • Thioredoxin-Disulfide Reductase
  • Organometallic Compounds
  • Gold