Cu(II) complex that synergistically potentiates cytotoxicity and an antitumor immune response by targeting cellular redox homeostasis
成果类型：
Article
署名作者：
Huang, Ke-Bin; Wang, Feng-Yang; Lu, Yuan; Yang, Liang- Mei; Long, Nian; Wang, Shan - Shan; Xie, Zhiying; Levine, Matthew; Zou, Taotao; Sessler, Jonathan L.; Liang, Hong
署名单位：
Guangxi Normal University; Sun Yat Sen University; University of Texas System; University of Texas Austin
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-11618
DOI：
10.1073/pnas.2404668121
发表日期：
2024-06-11
关键词：
oxidative stress
cancer-cells
death
induction
摘要：
Developing anticancer drugs with low side effects is an ongoing challenge. Immunogenic cell death (ICD) has received extensive attention as a potential synergistic modality for cancer immunotherapy. However, only a limited set of drugs or treatment modalities can trigger an ICD response and none of them have cytotoxic selectivity. This provides an incentive to explore strategies that might provide more effective ICD inducers free of adverse side effects. Here, we report a metal- based complex (Cu- 1) that disrupts cellular redox homeostasis and effectively stimulates an antitumor immune response with high cytotoxic specificity. Upon entering tumor cells, this Cu(II) complex enhances the production of intracellular radical oxidative species while concurrently depleting glutathione (GSH). As the result of heightening cellular oxidative stress, Cu- 1 gives rise to a relatively high cytotoxicity to cancer cells, whereas normal cells with low levels of GSH are relatively unaffected. The present Cu(II) complex initiates a potent ferroptosis- dependent ICD response and effectively inhibits in vivo tumor growth in an animal model (c57BL/6 mice challenged with colorectal cancer). This study presents a strategy to develop metal- based drugs that could synergistically potentiate cytotoxic selectivity and promote apoptosis- independent ICD responses through perturbations in redox homeostasis.