Dithiocarbazate-Copper Complexes for Bioimaging and Treatment of Pancreatic Cancer

Abstract

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)] <b>1</b>, [Cu^II₂(L)₂(NO₃)₂] <b>2</b>, and [Cu^II₂Cu^I(L)₂(Br)₃] <b>3</b>}, to assess their antipancreatic cancer activities. Complexes <b>1-3</b> 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 <b>3</b> was primarily localized in the mitochondria. Primarily, compound <b>3</b> also can be applied to <i>in vivo</i> imaging. Further studies revealed that complex <b>3</b> kills pancreatic cancer cells by triggering multiple mechanisms, including ferroptosis. Complex <b>3</b> 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.