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

Mol Cancer Ther. 2014 Aug;13(8):1979-90. doi: 10.1158/1535-7163.MCT-13-0963. Epub 2014 Jun 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Caspases / metabolism
  • Cell Survival / drug effects
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • Histone Deacetylase Inhibitors / pharmacology*
  • 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


  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Histone Deacetylase Inhibitors
  • OSU-HDAC42 compound
  • Phenylbutyrates
  • Sesquiterpenes
  • parthenolide
  • Caspases