Two clinical drugs deubiquitinase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trigger synergistic anti-tumor effects in vitro and in vivo

// Hongbiao Huang 1, * , Yuning Liao 1, * , Ningning Liu 1, 2 , Xianliang Hua 1 , Jianyu Cai 1 , Changshan Yang 1 , Huidan Long 1 , Chong Zhao 1 , Xin Chen 1 , Xiaoying Lan 1 , Dan Zang 1 , Jinjie Wu 1 , Xiaofen Li 1 , Xianping Shi 1 , Xuejun Wang 1, 3 , Jinbao Liu 1 1 State Key Laboratory of Respiratory Disease, Protein Modification and Degradation Laboratory, Department of Pathophysiology, Guangzhou Medical University, Guangdong 511436, People’s Republic of China 2 Guangzhou Research Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangdong 510260, People’s Republic of China 3 Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota 57069, USA * These authors contributed equally to this work Correspondence to: Hongbiao Huang, e-mail: hhb800616@126.com Jinbao Liu, e-mail: jliu@gzhmu.edu.cn Keywords: auranofin, deubiquitinase inhibitor, disulfiram, anticancer strategy Received: August 10, 2015      Accepted: November 16, 2015      Published: November 28, 2015 ABSTRACT Inhibition of proteasome-associated deubiquitinases (DUBs) is emerging as a novel strategy for cancer therapy. It was recently reported that auranofin (Aur), a gold (I)-containing compound used clinically to treat rheumatoid arthritis, is a proteasome-associated DUB inhibitor. Disulfiram (DSF), an inhibitor of aldehyde dehydrogenase, is currently in clinical use for treating alcoholism. Recent studies have indicated that DSF can also act as an antitumor agent. We investigated the effect of combining DSF and Aur on apoptosis induction and tumor growth in hepatoma cancer cells. Here we report that (i) the combined treatment of Aur and DSF results in synergistic cytotoxicity to hepatoma cells in vitro and in vivo ; (ii) Aur and DSF in combination induces caspase activation, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) production; (iii) pan-caspase inhibitor z-VAD-FMK could efficiently block apoptosis but not proteasome inhibition induced by Aur and DSF combined treatment, and ROS is not required for Aur+DSF to induce apoptosis. Collectively, we demonstrate a model of synergism between DSF and proteasome-associated DUB inhibitor Aur in the induction of apoptosis in hepatoma cancer cells, identifying a potential novel anticancer strategy for clinical use in the future.