Oncotarget

Research Papers:

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, Ping Q. Dou, Xuejun Wang and Jinbao Liu

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Oncotarget. 2014; 5:9118-9132. https://doi.org/10.18632/oncotarget.2361

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Abstract

Xin Chen1*, Xianping Shi1*, Chong Zhao1*, Xiaofen Li1, Xiaoying Lan1, Shouting Liu1, Hongbiao Huang1, Ningning Liu1,2, Siyan Liao1, Dan Zang1, Wenbin Song1, Quentin Liu3, Bing Z. Carter4, Q. Ping Dou1,5, Xuejun Wang1,6, Jinbao Liu1

1 State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China

2 Guangzhou Research Institute of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, People’s Republic of China

3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China

4 Section of Molecular Hematology and Therapy, Department of leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

5 The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201-2013, USA

6 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:

Dr. Jinbao Liu, email: [email protected]

Key words: Auranofin, proteasome, chronic myelogenous leukemia, imatinib resistance, Bcr-Abl

Received: July 24, 2014     Accepted: August 17, 2014     Published: August 22, 2014

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.


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