Dithiocarbazate-Copper Complexes for Bioimaging and Treatment of Pancreatic Cancer

Anticancer agents that present nonapoptotic cell death pathways are required for treating apoptosis-resistant pancreatic cancer. Here, we synthesized three fluorescent dithiocarbazate–copper complexes, {[Cu^II(L)­(Cl)] 1, [Cu^II₂(L)₂(NO₃)₂] 2, and [Cu^II₂Cu^I(L)₂(Br)₃] 3}, to assess their antipancreatic cancer activities. Complexes 1–3 showed significantly greater cytotoxicity toward several pancreatic cancer cell lines with better IC₅₀ than those of the HL ligand and cisplatin. Confocal fluorescence imaging showed that complex 3 was primarily localized in the mitochondria. Primarily, compound 3 also can be applied to in vivo imaging. Further studies revealed that complex 3 kills pancreatic cancer cells by triggering multiple mechanisms, including ferroptosis. Complex 3 is the first copper complex to evoke cellular events consistent with ferroptosis in cancer cells. Finally, it significantly retarded the ASPC-1 cells’ growth in a mouse xenograft model.