Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: a novel potential strategy in acute myelogenous leukemia

Most patients with acute myelogenous leukemia (AML) relapse and die of their disease. Increasing evidence indicates that AML relapse is driven by the inability to eradicate leukemia stem cells (LSC). Thus, it is imperative to identify novel therapies that can ablate LSCs. Using an in silico gene exp...

Full description

Saved in:
Bibliographic Details
Published in:Molecular cancer therapeutics 2014-08, Vol.13 (8), p.1979-1990
Main Authors: Guzman, Monica L, Yang, Neng, Sharma, Krishan K, Balys, Marlene, Corbett, Cheryl A, Jordan, Craig T, Becker, Michael W, Steidl, Ulrich, Abdel-Wahab, Omar, Levine, Ross L, Marcucci, Guido, Roboz, Gail J, Hassane, Duane C
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Caspases - metabolism
Cell Survival - drug effects
Histone Deacetylase Inhibitors - pharmacology
HSP90 Heat-Shock Proteins - antagonists & inhibitors
Humans
Lethal Dose 50
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - pathology
Mice, Inbred NOD
Mice, SCID
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - physiology
Phenylbutyrates - pharmacology
Sesquiterpenes - pharmacology
Transcriptome
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Most patients with acute myelogenous leukemia (AML) relapse and die of their disease. Increasing evidence indicates that AML relapse is driven by the inability to eradicate leukemia stem cells (LSC). 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, we identified AR-42 (OSU-HDAC42), a novel histone deacetylase inhibitor that is structurally similar to phenylbutyrate, but with improved activity at submicromolar concentrations. Here, we report that AR-42 induces NF-κB inhibition, disrupts the ability of Hsp90 to stabilize its oncogenic clients, and causes potent and specific cell death of LSCs but not normal hematopoietic stem and progenitor cells. Unlike parthenolide, 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.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-13-0963