Abstract 2145: AR-42, a novel histone deacetylase inhibitor with selectivity against leukemia stem cell via apoptosis induction, inhibition of chaperone function of heat shock protein 90 in acute myeloid leukemia

Abstract

Abstract AML is a fatal disease where most patients relapse and die of their disease. Increasing evidence indicates that disease relapse is driven by leukemia stem cells (LSCs). Thus, it is imperative to identify new therapies that can ablate LSCs. We have previously reported that screening the NCBI Gene Expression Omnibus (GEO) can accelerate the identification of anti-LSC compounds by searching for those mimicking the gene expression pattern of a known anti-LSC compound, parthenolide (PTL). One of our “hits” was the HDACi, AR-42 (Arno Therapeutics, Inc). This compound represents a novel class of HDACis that are structurally similar to phenylbutyrate, but with improved HDACi activity at sub-micromolar concentrations. At first, we investigated effects of AR-42 on growth and colony forming ability by using AML cell lines and primary human AML samples. AR-42 exhibits low micromolar potency in biochemical and cellular assays. AR-42 efficiently suppressed AML cell growth at a low dosage (1 μM) after 24 hours of treatment. Just like PTL, AR-42 preferentially targets AML progenitor and stem cell populations. More than 50% cell death was induced by AR-42 in phenotypically defined AML stem / progenitor. Colony forming capability of LSCs treated with 1 μM AR-42 for 24 hours was significantly diminished. Furthermore, 1 μM AR-42 significantly impaired the potential of LSCs in a nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model. Surprisingly, even though AR-42 partially mimics the gene expression pattern of PTL, it does not activate Nrf2-controlled cytoprotective responses like PTL. AR- 42 inhibits NF-κB but, unlike PTL, does not activate HMOX-1. AR-42- mediated apoptosis is associated with activation of caspase 8, PARP cleavage. Further studies found that AR-42 induced inhibition of HSP90 in conjunction with degradation of FLT3 protein. Altogether, these findings indicate that AR-42 may be a promising LSC-targeted therapeutic agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2145. doi:10.1158/1538-7445.AM2011-2145