Using copper-ionophores to translocate extracellular copper into mitochondria is a clinically validated anticancer strategy that has been identified as a new type of regulated cell death termed “cuproptosis.” This study reports a mitochondria-targeting Cu(I) complex, Cu(I)Br(PPh₃)₃ (CBP), consisting of a cuprous ion coordinated by three triphenylphosphine moieties and a Br atom. CBP exhibited antitumor and antimetastatic efficacy in vitro and in vivo by specifically targeting mitochondria instigating mitochondrial dysfunction. The cytotoxicity of CBP could only be reversed by a copper chelator rather than inhibitors of the known cell death, indicating copper-dependent cytotoxicity. Furthermore, CBP induced the oligomerization of lipoylated proteins and the loss of Fe–S cluster proteins, consistent with characteristic features of cuproptosis. Additionally, CBP induced remarkable intracellular generation of reactive oxygen species (ROS) through a Fenton-like reaction, indicating a complex antitumor mechanism. This is a proof-of-concept study exploiting the antitumor activity and mechanism of the Cu(I)-based mitochondria-targeting therapy.

中文翻译：

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线粒体靶向 Cu(I) 复合物的抗肿瘤活性和机制见解


使用铜离子载体将细胞外铜转移到线粒体中是一种经过临床验证的抗癌策略，已被确定为一种新型的调节性细胞死亡，称为“铜中毒”。本研究报告了一种靶向线粒体的 Cu(I) 络合物，Cu(I)Br(PPh ₃ ) ₃ (CBP)，由三个三苯基膦部分协调的亚铜离子和一个 Br 原子。 CBP 通过特异性靶向引发线粒体功能障碍的线粒体，在体外和体内表现出抗肿瘤和抗转移功效。 CBP 的细胞毒性只能被铜螯合剂逆转，而不能被已知细胞死亡的抑制剂逆转，这表明铜依赖性细胞毒性。此外，CBP 诱导脂酰化蛋白的寡聚化和 Fe-S 簇蛋白的丢失，这与铜凋亡的特征一致。此外，CBP 通过类芬顿反应诱导细胞内显着产生活性氧 (ROS)，这表明其具有复杂的抗肿瘤机制。这是一项利用基于 Cu(I) 的线粒体靶向治疗的抗肿瘤活性和机制的概念验证研究。