title: Novel use of old drug: Anti-rheumatic agent auranofin overcomes imatinib-resistance of chronic myeloid leukemia cells.
abstract: Patients with chronic myeloid leukemia (CML) are commonly treated with a specific inhibitor of BCR-ABL tyrosine kinase, imatinib mesylate (IM). Unfortunately, CML patients develop IM-resistance, which has emerged as a significant clinical problem. Somatic mutations, especially T315I mutation, in BCR-ABL kinase domain represent the most common mechanism underlying drug resistance to tyrosine kinase inhibitors (TKI), including imatinib. Thus, it is urgent to develop novel therapeutic strategies to overcome TKI-resistance. The anti-rheumatic gold (I) compound Auranofin (AF), was recently approved by US Food and Drug Administration for Phase II clinical trials to treat leukemia. In a recent study, we discovered that AF can selectively inhibit 19S proteasome-associated deubiquitinases (UCHL5 and USP14), which mediates its anticancer effects. More recently studies we have shown that AF inhibits the growth of both Bcr-Abl wild-type cells and IM-resistant Bcr-Abl-T315I mutation cellsin vitroandin vivo. AF-induced Bcr-Abl down regulation is associated with diminished mRNA expression and caspase-dependent Bcr-Abl cleavage. More importantly, we unraveled that AF cytotoxicity is mediated by proteasome inhibition rather than previously suspected reactive oxygen species (ROS) generation. These findings support that AF overcomes IM-resistance through Bcr/Abl-dependent and -independent mechanisms, identifying a potentially new strategy for cancer treatment.
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Xianping
authors.initials: X
authors.lastname: Shi
authors.affiliation: State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, 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, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
keywords: Bcr-Abl; CML; auranofin; imatinib resistance; proteasomal deubiquitinases; reactive oxygen species