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.

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing

“…Since Aur also has anti-cancer effects with less toxicity compared to currently used chemotherapeutic agents, Aur was recently approved by FDA for Phase II clinical trial in cancer therapy [108,109]. Even though several potential molecular targets for the anti-inflammatory and anti-cancer activities of Aur have been reported, only recently it was found that Aur inhibits the 26S proteasome but not 20S proteasome peptidases , a mechanism different from the FDA-approved proteasome inhibitor bortezomib [110–112]. Molecularly, Aur inhibits 19S-associated DUBs USP14 and UCHL5 [111, 112].…”

Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling

“…TrxR inhibition was attributed to structural modification occurring, upon cofactor binding, with auranofin's gold(I) coordination to the active site selenocysteine (29,31,62,75). An alternate mechanism has been described for gold(III) compounds through oxidative protein damage and inhibition of the ubiquitinproteasome system by targeting deubiquitinases involved in cell cycle regulation, protein degradation, gene expression, and DNA repair (15,57). Both these mechanisms of action result in apoptosis.…”

“…Elevated GSH has been associated with cancer cell resistance to various cytotoxic agents (14,15). Thus, lowering GSH has been sought by specific inhibition of c-glutamylcysteine ligase, a key enzyme of GSH biosynthesis.…”

Inhibition of 19S proteasome-associated deubiquitinases by metal-containing compounds

“…Moreover, auranofin can selectively induce cytotoxicity in primary monocytes from patients with AML (average 24h IC50=0.159 μM while CTR=0.622 μM). Furthermore, our recent study reveals that auranofin overcomes Imatinib mesylate resistance through both Bcr/Abl-dependent and -independent mechanisms, and proteasome inhibition but not ROS is required for auranofin-induced caspase activation and apoptosis [99]. …”