Thiosemicarbazone Mixed-Valence Cu(I/II) Complex against Lung Adenocarcinoma Cells through Multiple Pathways Involving Cuproptosis

Induction of cuproptosis and targeting of multiple signaling pathways show promising applications in tumor therapy. In this study, we synthesized two thiosemicarbazone-copper complexes ([Cu^II(L)Cl] 1 and [Cu^II₂Cu^I(L)₂Cl₃] 2, where HL is the (E)-N-methyl-2-(phenyl(pyridin-2-yl)methylene ligand), to assess their antilung cancer activities. Both copper complexes showed better anticancer activity than cisplatin and exhibited hemolysis comparable to that of cisplatin. In vivo experiments showed that complex 2 retarded the A549 cell growth in a mouse xenograft model with low systemic toxicity. Primarily, complex 2 kills lung cancer cells in vitro and in vivo by triggering multiple pathways, including cuproptosis. Complex 2 is the first mixed-valent Cu(I/II) complex to induce cellular events consistent with cuproptosis in cancer cells, which may stimulate the development of mixed-valent copper complexes and provide effective cancer therapy.