Antitumor Activity and Mechanistic Insights of a Mitochondria-Targeting Cu(I) Complex

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.