A mitochondrion-targeting copper complex exhibits potent cytotoxicity against cisplatin-resistant tumor cells through multiple mechanisms of action

Abstract

Copper complexes are potential anticancer drugs by virtue of their available redox properties and low toxicity. In this study, a copper(II) complex, [Cu(ttpy-tpp)Br₂]Br (simplified as CTB, ttpy-tpp = 4′-p-tolyl-(2,2′:6′,2′′-terpyridyl)triphenylphosphonium bromide), is synthesized and characterized by X-ray crystallography and ESI-MS as a targeted anticancer agent. Triphenylphosphine (TPP) is introduced into the complex for its mitochondrion-targeting ability and lipophilic character. The uptake of CTB by tumor cells and mitochondria was determined by ICP-MS or fluorescence spectrometry. CTB is able to cross the cytoplasmic and mitochondrial membranes of tumor cells and influence the mitochondrial membrane potential more profoundly than the anticancer drug cisplatin. The cytotoxicity of CTB was tested on MCF-7, HeLa, Skov-3, A549 and cisplatin-resistant A549R tumor cells by MTT assay. CTB is more cytotoxic against these cells than cisplatin; particularly, it is highly effective against cisplatin-resistant tumor cells. The interaction between CTB and DNA has been studied by spectroscopic methods and agarose gel electrophoresis. CTB strongly interacts with DNA via intercalation stabilized by electrostatic forces, and displays a significant cleavage activity towards supercoiled pBR322 DNA and cellular DNA through an oxidative mechanism. The cytotoxicity of CTB seems to result from multiple mechanisms of action, including the modification of DNA conformation, generation of reactive oxygen species, scission of DNA strands, and dissipation of mitochondrial membrane potential. The delocalized cationic property and high hydrophilicity of CTB favours its selective accumulation in cancer cells and mitochondria. This study demonstrates that copper complexes with mitochondrion-targeting function could be efficient anticancer drugs immune to the drug resistance of cisplatin.