The Novel Deacetylase Inhibitor AR-42 Demonstrates Pre-Clinical Activity in B-Cell Malignancies In Vitro and In Vivo

Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
PLoS ONE (Impact Factor: 3.53). 06/2010; 5(6):e10941. DOI: 10.1371/journal.pone.0010941
Source: PubMed

ABSTRACT While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies.
In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC(50) (50% growth inhibitory concentration) of AR-42 is 0.61 microM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC(50) (concentration lethal to 50%) of AR-42 is 0.76 microM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity.
Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Most patients with acute myeloid leukemia (AML) relapse and die of their disease. Increasing evidence indicates that AML relapse is driven by the inability to eradicate leukemia stem cells (LSCs). 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 (PTL), we identified AR-42 (OSU-HDAC42), a novel histone deacetylase inhibitor (HDACi) that is structurally similar to phenylbutyrate, but with improved activity at sub-micromolar concentrations. Here, we report that AR-42 induces NF-κB inhibition, disrupts the ability of heat shock protein 90 (Hsp90) to stabilize its oncogenic clients, and causes potent and specific cell death of LSCs but not normal hematopoietic stem and progenitor cells. Unlike PTL, 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.
    Molecular Cancer Therapeutics 06/2014; 13(8). DOI:10.1158/1535-7163.MCT-13-0963 · 6.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sphingosine kinase 2 (SK2) may have utility as a prognostic marker in inflammatory diseases such as cancer where it has been rationalized as candidate therapeutic target. Here we show that SK2 has an oncogenic role in acute lymphoblastic leukemia (ALL) by influencing expression of MYC. Genetic ablation of SK2 impaired leukemia development in a mouse model of ALL and pharmacological inhibition extended survival in mouse xenograft models of human disease. SK2 attenuation in both settings reduced MYC expression in leukemic cells, with reduced levels of acetylated histone H3 within the MYC gene associated with reduced levels of MYC protein and expression of MYC regulated genes. Our results demonstrated that SK2 regulates MYC, which has a pivotal role in hematological malignancies, providing a preclinical proof of concept for this pathway as a broad-based therapeutic target in this setting.
    Cancer Research 03/2014; 74(10). DOI:10.1158/0008-5472.CAN-13-2732 · 9.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mouse models that recapitulate human malignancy are valuable tools for the elucidation of the underlying pathogenetic mechanisms and for pre-clinical studies. Several genetically-engineered mouse models have been generated, either mimicking genetic aberrations or deregulated gene expression in chronic lymphocytic leukemia (CLL). The usefulness of such models in the study of the human disease may potentially be hampered by species-specific biological differences in the target cell of the oncogenic transformation. Specifically, do the genetic lesions or the deregulated expression of leukemia-associated genes faithfully recapitulate the spectrum of lymphoproliferations in humans? Do the CLL-like lymphoproliferations in the mouse have the phenotypic, histological, genetic, and clinical features of the human disease? We here compare the various CLL mouse models with regard to disease phenotype, penetrance and severity. We discuss similarities and differences of the murine lymphoproliferations compared to human CLL. We propose that the Eμ-TCL1 transgenic and 13q14-deletion models that have been comprehensively studied at the levels of leukemia phenotype, antigen-receptor repertoire and disease course, show close resemblance to the human disease. We conclude that modelling CLL-associated genetic dysregulations in mice can provide important insights into the molecular mechanisms of disease pathogenesis and generate valuable tools for the development of novel therapies.
    Blood 07/2014; 124(7). DOI:10.1182/blood-2014-05-577122 · 9.78 Impact Factor

Full-text (3 Sources)

Available from
May 22, 2014