Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: a novel potential strategy in acute myeloid leukemia
Menée in vitro, cette étude met en évidence des mécanismes par lesquels, via l'inhibition de NF-kappaB, un nouvel inhibiteur d'histone désacétylase (AR-42) est susceptible d'éradiquer les cellules souches de leucémie myéloïde aiguë
Most patients with acute myeloid leukemia (AML) relapse and die of their disease. Increasing evidence indicates that AML relapse is driven by the inability to eradicate leukemia stem cells (LSCs). Thus, it is imperative to identify novel therapies that can ablate LSCs. Using an in silico gene expression-based screen for compounds evoking transcriptional effects similar to the previously described anti-LSC agent parthenolide (PTL), we identified AR-42 (OSU-HDAC42), a novel histone deacetylase inhibitor (HDACi) that is structurally similar to phenylbutyrate, but with improved activity at sub-micromolar concentrations. Here, we report that AR-42 induces NF-κB inhibition, disrupts the ability of heat shock protein 90 (Hsp90) to stabilize its oncogenic clients, and causes potent and specific cell death of LSCs but not normal hematopoietic stem and progenitor cells. Unlike PTL, the caspase-dependent apoptosis caused by AR-42 occurs without activation of Nrf-2 driven cytoprotective pathways. As AR-42 is already being tested in early clinical trials, we expect that our results can be extended to the clinic.
http://mct.aacrjournals.org/content/early/2014/06/14/1535-7163.MCT-13-0963.abstract