Citation: Linping Zhao, Jianqiao Li, Guangmiao Chen, Chuyu Huang, Hangyu Zhou, Rongrong Zheng, Youqin Xu, Xueyan Jiang, Xiaohui Chen, Shiying Li. Cuproptosis amplifier of copper-telaglenastat coordinate to trigger cell ferroptosis for synergistic breast cancer suppression[J]. Chinese Chemical Letters, ;2026, 37(1): 110959. doi: 10.1016/j.cclet.2025.110959 shu

Cuproptosis amplifier of copper-telaglenastat coordinate to trigger cell ferroptosis for synergistic breast cancer suppression

Linping Zhao ^{a, 1,*,} ,
Jianqiao Li ^{b, 1} ,
Guangmiao Chen ^{c, 1} ,
Chuyu Huang ^c ,
Hangyu Zhou ^a ,
Rongrong Zheng ^c ,
Youqin Xu ^a ,
Xueyan Jiang ^c ,
Xiaohui Chen ^{b, *,} ,
Shiying Li ^{c, *,}

a.
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510700, China
b.
Department of Emergency, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
c.
Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China

zlp2022@gzhmu.edu.cn

cxhgz168paper@163.com

lisy-sci@gzhmu.edu.cn

Received Date: 19 September 2024
Revised Date: 11 February 2025
Accepted Date: 14 February 2025
Available Online: 15 February 2025

Figures(6)

Metal ion homeostasis plays a pivotal role in maintaining cellular functions, and its disruption can initiate regulated cell death pathways. Despite its therapeutic potential, metal ion therapy for breast cancer has been hampered by inefficient ion delivery and the intrinsic resistance mechanisms of cancer cells. In this work, a cuproptosis amplifier of copper-telaglenastat coordinate (denoted as Cu-CB) is developed to trigger cell ferroptosis for synergistic breast cancer treatment. Telaglenastat (CB-839), a glutaminase inhibitor, is identified as an effective copper ionophore that facilitates the formation of Cu-CB. Specially, Cu-CB can promote the aggregation of lipoylated proteins to initiate cuproptosis, while also inhibiting glutathione (GSH) synthesis and downregulating glutathione peroxidase 4 (GPX4) to trigger ferroptosis. The interplay between these cuproptosis and apoptosis pathways, mediated by Cu-CB, significantly amplifies reactive oxygen species (ROS) production and lipid peroxidation, culminating in the synergistic suppression of breast cancer. Both in vitro and in vivo studies validate the superior antitumor effects of Cu-CB through the induction of cuproptosis and ferroptosis, which may provide a new insight for metal ion delivery systems and metal ion-based tumor therapies.
- Cooper ionophore,
- Telaglenastat,
- Metal ion delivery,
- Cuproptosis,
- Ferroptosis
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