Abstract
BackgroundWhile 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.Principal FindingsIn mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC50 (50% growth inhibitory concentration) of AR-42 is 0.61 µM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC50 (concentration lethal to 50%) of AR-42 is 0.76 µM. 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.Conclusions/SignificanceTogether, 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.
Highlights
Deacetylases (DACs) are a family of enzymes that catalyze the removal of acetyl groups from lysine residues, and to date have been extensively studied in the context of histone proteins
In vitro activity of AR-42 In MTT assays, the 50% growth inhibitory concentration (IC50) of AR-42 at 48 hr was 0.61 mM in Raji Burkitt’s lymphoma cells, 0.22 mM in 697 acute lymphoblastic leukemia cells, and 0.21 mM in JeKo-1 Mantle cell lymphoma (MCL) cells (n = 3 each)
Unlike other compounds whose efficacy is influenced by human serum protein binding, we found that AR-42 has similar cytotoxic effect regardless of whether human or bovine serum matrices are used
Summary
Deacetylases (DACs) are a family of enzymes that catalyze the removal of acetyl groups from lysine residues, and to date have been extensively studied in the context of histone proteins Inhibitors of these enzymes were originally reported to relieve transcriptional repression and subsequent epigenetic silencing caused by histone deacetylation. DAC6 is a cytoplasmic enzyme that deacetylates tubulin [1], HSP90 [2,3], and likely additional cytoplasmic proteins Due to their broad effects on gene transcription, cell growth and differentiation, inhibitors of DACs have been shown to possess anti-cancer activity in a variety of tumor cell models, in primary tumor cells, and in vivo [4,5,6]. We investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies
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