title: Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms.
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.
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China; These Authors contributed equally to this work.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China; These Authors contributed equally to this work.
authors.forename: Xianping
authors.initials: X
authors.lastname: Shi
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China; These Authors contributed equally to this work.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Lan
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Shouting
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China; Guangzhou Research Institute of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, People's Republic of China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Siyan
authors.initials: S
authors.lastname: Liao
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Song
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Section of Molecular Hematology and Therapy, Department of leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Bing Z
authors.initials: BZ
authors.lastname: Carter
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China; 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.
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China; Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota 57069, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Departments of Pathophysiology and Biochemistry, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001310:Auranofin / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D018501:Antirheumatic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C509299:USP14 protein, human; D001310:Auranofin; D000068877:Imatinib Mesylate; D013880:Thioredoxin-Disulfide Reductase; D016044:Fusion Proteins, bcr-abl; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase