Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells

A novel potential strategy in acute myelogenous leukemia

Monica L. Guzman, Neng Yang, Krishan K. Sharma, Marlene Balys, Cheryl A. Corbett, Craig T. Jordan, Michael W. Becker, Ulrich G. Steidl, Omar Abdel-Wahab, Ross L. Levine, Guido Marcucci, Gail J. Roboz, Duane C. Hassane

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1979-1990
Number of pages12
JournalMolecular Cancer Therapeutics
Volume13
Issue number8
DOIs
StatePublished - 2014

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Histone Deacetylase Inhibitors
Hematopoietic Stem Cells
Acute Myeloid Leukemia
Leukemia
Stem Cells
Phenylbutyrates
Recurrence
Caspases
Computer Simulation
Cell Death
Clinical Trials
Apoptosis
Gene Expression
parthenolide
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells : A novel potential strategy in acute myelogenous leukemia. / Guzman, Monica L.; Yang, Neng; Sharma, Krishan K.; Balys, Marlene; Corbett, Cheryl A.; Jordan, Craig T.; Becker, Michael W.; Steidl, Ulrich G.; Abdel-Wahab, Omar; Levine, Ross L.; Marcucci, Guido; Roboz, Gail J.; Hassane, Duane C.

In: Molecular Cancer Therapeutics, Vol. 13, No. 8, 2014, p. 1979-1990.

Research output: Contribution to journalArticle

Guzman, ML, Yang, N, Sharma, KK, Balys, M, Corbett, CA, Jordan, CT, Becker, MW, Steidl, UG, Abdel-Wahab, O, Levine, RL, Marcucci, G, Roboz, GJ & Hassane, DC 2014, 'Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: A novel potential strategy in acute myelogenous leukemia', Molecular Cancer Therapeutics, vol. 13, no. 8, pp. 1979-1990. https://doi.org/10.1158/1535-7163.MCT-13-0963
Guzman, Monica L. ; Yang, Neng ; Sharma, Krishan K. ; Balys, Marlene ; Corbett, Cheryl A. ; Jordan, Craig T. ; Becker, Michael W. ; Steidl, Ulrich G. ; Abdel-Wahab, Omar ; Levine, Ross L. ; Marcucci, Guido ; Roboz, Gail J. ; Hassane, Duane C. / Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells : A novel potential strategy in acute myelogenous leukemia. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 8. pp. 1979-1990.
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