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

   

Authors:	Guzman, M. L.; Yang, N.; Sharma, K. K.; Balys, M.; Corbett, C. A.; Jordan, C. T.; Becker, M. W.; Steidl, U.; Abdel-Wahab, O.; Levine, R. L.; Marcucci, G.; Roboz, G. J.; Hassane, D. C.
Article Title:	Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: A novel potential strategy in acute myelogenous leukemia
Abstract:	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. ©2014 AACR.
Keywords:	controlled study; unclassified drug; acute granulocytic leukemia; human cell; histone deacetylase inhibitor; nonhuman; cancer patient; mouse; apoptosis; gene expression profiling; animal experiment; animal model; immunoglobulin enhancer binding protein; genetic transcription; antineoplastic activity; drug potency; drug selectivity; cancer stem cell; heat shock protein 90; leukemia relapse; cell protection; concentration response; leukemia stem cell; arylbutyric acid derivative; parthenolide; transcription factor nrf2; human; priority journal; article; ar 42
Journal Title:	Molecular Cancer Therapeutics
Volume:	13
Issue:	8
ISSN:	1535-7163
Publisher:	American Association for Cancer Research
Date Published:	2014-08-01
Start Page:	1979
End Page:	1990
Language:	English
DOI:	10.1158/1535-7163.mct-13-0963
PROVIDER:	scopus
PUBMED:	24934933
PMCID:	PMC4383047
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84905638003&partnerID=40&md5=5eb1da8fded46279a722d723af450cfd
Notes:	Export Date: 2 September 2014 -- CODEN: MCTOC -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/58024