Copper(<scp>ii</scp>) complex enhanced chemodynamic therapy through GSH depletion and autophagy flow blockade
Wen‐Ying Shen, Chun‐Peng Jia, Li-Yi Liao, Liu‐Lin Chen, Cheng-Cheng Yuan, Yun‐Qiong Gu, Yang-Han Liu, Hong Liang, Zhen‐Feng Chen
Abstract
Three copper(II) complexes C1-C3 were synthesized and fully characterized as chemodynamic therapy (CDT) anticancer agents. C1-C3 showed greater cytotoxicity than their ligands toward SK-OV-3 and T24 cells. Particularly, C2 showed high cytotoxicity toward T24 cells and low cytotoxicity toward normal human HL-7702 and WI-38 cells. Mechanistic studies demonstrated that C2 oxidized GSH to GSSG and produced ˙OH, which induced mitochondrial dysfunction and ER stress, finally leading to apoptosis of T24 cells. In addition, C2 inhibited autophagy by blocking autophagy flow, thereby closing the self-protection pathway of oxidative stress to enhance CDT. Importantly, C2 significantly inhibited T24 tumor growth with 57.1% inhibition in a mouse xenograft model. C2 is a promising lead as a potential CDT anticancer agent.