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-kB 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 caspasedependent 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. Mol Cancer Ther; 13(8); 1979-90. Ó2014 AACR.

Biology and Clinical Relevance of Acute Myeloid Leukemia Stem Cells

“…In addition to proteasome inhibitors like MG-132, other compounds with inhibitory activity against NF-κB including parthenolide (PTL) [49], AR-42 [50], and niclosamide [51] have also be reported to target primitive AML cells. PTL is the major active compound in the herbal medicine Feverfew ( Tanacetum parthenium ) and is one of the first compounds shown to selectively ablate LSCs without significant toxicity to normal HSPCs [49, 52].…”

The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

“…At sub mM concentrations, this novel HDAC inhibitor was shown to exert anti-proliferative and cytotoxic activities against lymphocytic/acute myeloid leukemia cells, and B-cell lymphoma cells [9e12]. Studies have also shown that AR-42 could directly target leukemic stem cells [10]. However, the potential activity of AR-42 in colon cancer cells is not extensively studied, and the underling mechanisms need further characterizations.…”

Parthenolide and DMAPT induce cell death in primitive CML cells through reactive oxygen species

“…Total p65 protein levels remained unchanged after treatment, while phospho‐p65 levels diminished with PTL treatments in both CML cell lines and in a primitive population from a CML patient, indicating an inhibition of the NF‐κB canonical pathway (Figure 5B). Furthermore, to verify the functional status of NF‐κB, transcriptional activity of the pathway was evaluated in CML cell lines (K562, Meg‐01, KCL‐22, Kasumi‐4), AML cell line HL60 and primary CD34 + lin − cells from CML and NBM samples, according to Guzman and collaborators 22. Cells were cultured for 6 hours in the absence or presence of PTL or DMAPT at 7.5 μmol/L.…”