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 ([CuII(L)Cl] 1 and
[CuII2CuI(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.