Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms. 2519 54

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 cells in vitro and in 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.
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PMID:Novel use of old drug: Anti-rheumatic agent auranofin overcomes imatinib-resistance of chronic myeloid leukemia cells. 2599 93