Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms

Xin Chen, Xianping Shi, Chong Zhao, Xiaofen Li, Xiaoying Lan, Shouting Liu, Hongbiao Huang, Ningning Liu, Siyan Liao, Dan Zang, Wenbin Song, Quentin Liu, Bing Z. Carter, Q. Ping Dou, Xuejun Wang, Jinbao Liu

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Resistance to Imatinib mesylate (IM) is an emerging problem for patients with chronic myelogenous leukemia (CML). T315I mutation in the Bcr-Abl is the predominant mechanism of the acquired resistance to IM and second generation tyrosine kinase inhibitors (TKI). Therefore it is urgent to search for new measures to overcome TKI-resistance. Auranofin (AF), clinically used to treat rheumatic arthritis, was recently approved by US Food and Drug Administration for Phase II clinical trial to treat cancer. In contrast to the reports that AF induces apoptosis by increasing intracellular reactive oxygen species (ROS) levels via inhibiting thioredoxin reductase, our recent study revealed that AF-induced apoptosis depends on inhibition of proteasomal deubiquitinases (UCHL5 and USP14). Here we report that (i) AF induces apoptosis in both Bcr-Abl wild-type cells and Bcr-Abl-T315I mutation cells and inhibits the growth of IM-resistant Bcr-Abl-T315I xenografts in vivo; (ii) AF inhibits Bcr-Abl through both downregulation of Bcr-Abl gene expression and Bcr-Abl cleavage mediated by proteasome inhibition-induced caspase activation; (iii) proteasome inhibition but not ROS is required for AF-induced caspase activation and apoptosis. These findings support that AF overcomes IM resistance through both Bcr/Abl-dependent and -independent mechanisms, providing great clinical significance for cancer treatment.

Original languageEnglish (US)
Pages (from-to)9118-9132
Number of pages15
JournalOncotarget
Volume5
Issue number19
DOIs
StatePublished - Jan 1 2014

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Keywords

  • Auranofin
  • Bcr-Abl
  • Chronic myelogenous leukemia
  • Imatinib resistance
  • Proteasome

ASJC Scopus subject areas

  • Oncology

Cite this

Chen, X., Shi, X., Zhao, C., Li, X., Lan, X., Liu, S., Huang, H., Liu, N., Liao, S., Zang, D., Song, W., Liu, Q., Carter, B. Z., Ping Dou, Q., Wang, X., & Liu, J. (2014). Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms. Oncotarget, 5(19), 9118-9132. https://doi.org/10.18632/oncotarget.2361