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

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

Research output: Contribution to journalArticle

32 Scopus citations

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 proteasomeassociated DUB inhibitor Aur in the induction of apoptosis in hepatoma cancer cells, identifying a potential novel anticancer strategy for clinical use in the future.

Original languageEnglish (US)
Pages (from-to)2796-2808
Number of pages13
JournalOncotarget
Volume7
Issue number3
DOIs
StatePublished - 2016

Keywords

  • Anticancer strategy
  • Auranofin
  • Deubiquitinase inhibitor
  • Disulfiram

ASJC Scopus subject areas

  • Oncology

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