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

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.
Authors	Hongbiao Huang, Yuning Liao, Ningning Liu, Xianliang Hua, Jianyu Cai, Changshan Yang, Huidan Long, Chong Zhao, Xin Chen, Xiaoying Lan, Dan Zang, Jinjie Wu, Xiaofen Li, Xianping Shi, Xuejun Wang, Jinbao Liu
Journal	Oncotarget (Oncotarget) Vol. 7 Issue 3 Pg. 2796-808 (Jan 19 2016) ISSN: 1949-2553 [Electronic] United States
PMID	26625200 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Amino Acid Chloromethyl Ketones Antineoplastic Agents Caspase Inhibitors Reactive Oxygen Species benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone Auranofin Aldehyde Dehydrogenase Poly(ADP-ribose) Polymerases Ubiquitin-Specific Proteases Caspases Disulfiram
Topics	Aldehyde Dehydrogenase (antagonists & inhibitors) Amino Acid Chloromethyl Ketones (pharmacology) Animals Antineoplastic Agents (pharmacology) Antineoplastic Combined Chemotherapy Protocols (pharmacology) Apoptosis (drug effects) Auranofin (pharmacology) Carcinoma, Hepatocellular (drug therapy) Caspase Inhibitors (pharmacology) Caspases (metabolism) Cell Line, Tumor Cell Survival Disulfiram (pharmacology) Drug Synergism Endoplasmic Reticulum Stress (drug effects) Enzyme Activation (drug effects) Hep G2 Cells Humans Liver Neoplasms (drug therapy) Mice Mice, Nude Poly(ADP-ribose) Polymerases (metabolism) Reactive Oxygen Species (metabolism) Ubiquitin-Specific Proteases (antagonists & inhibitors) Xenograft Model Antitumor Assays

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