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The novel histone deacetylase inhibitor NVP-LAQ824: an addition to the therapeutic armamentarium in leukemia?

Leukemia volume 18, pages 1931–1933 (2004)Cite this article

In the current issue of Leukemia, Weisberg et al1 describe the antileukemic properties of a novel histone deacetylase inhibitor (HDACI), NVP-LAQ824, in leukemia cells expressing the Bcr/Abl kinase as well as in their Bcr/Abl− counterparts. HDACIs represent a diverse group of compounds that block the actions of histone deacetylases (HDACs), enzymes that, in conjunction with histone acetylases (HATs), reciprocally regulate the acetylation status of histones, large globular proteins that form the core components of nucleosomes.2 Post-translational modifications in histones, including acetylation, phosphorylation, methylation, and ADP-ribosylation, comprise the components of an epigenetic mechanism by which gene transcription is regulated, and form what is collectively referred to as the histone code.3 Of the post-translational modifications involved in transcriptional regulation, acetylation of histones has been the most extensively studied. Acetylation of positively charged lysine residues in the N-terminal histone tail results in their neutralization, which allows chromatin to assume a more relaxed, open configuration as a consequence of diminished association with the negatively charged phosphate backbone of DNA. This leads, in most cases, to enhanced gene transcription, although inhibition of gene expression can also result.4 In addition to acetylation of chromatin at specific sites, which modifies protein interactions, HDACs also directly acetylate other proteins, including transcription factors and cell cycle-related proteins. In this way, HDACs exert effects distinct from their actions on chromatin structure and function. Moreover, HDACs are involved in transcriptional repression (eg, through participation in corepressor complexes) by oncogenic fusion proteins such as AML1-ETO, which has been implicated in leukemic transformation in certain subtypes of acute myeloid leukemia (AML) (eg those associated with the 8:21 translocation; M2).5 For these and other reasons, HDACs represent a very attractive target for pharmacologic intervention, particularly in the case of hematologic malignancies such as AML. Several broad categories of HDACIs have been developed for clinical usage, including short-chain fatty acids (eg, butyrate), hydroxamic acids (eg, suberoylanilide hydroxamic acid (SAHA)), cyclic tetrapeptides (eg, depsipeptide), and benzamides (eg, MS-275). Among the many genes whose expression is altered by HDACIs is p21CIP1, a cyclin-dependent kinase inhibitor critically involved in G1 arrest accompanying the differentiation process.6

One important issue remaining to be resolved is why under some circumstances HDACIs induce differentiation, while in others they trigger the apoptotic cascade. In leukemic cells, short-chain fatty acids such as butyrate or derivatives such as phenylbutyrate have long been known to induce leukemic cell maturation (eg, in murine erythroleukemia (MEL) cells),7 although an unfavorable pharmacokinetic/pharmacodynamic profile has limited the clinical utility of these agents. Subsequently, members of the hydroxamic acid class of HDACIs (eg, SAHA) have been developed which are nearly 3 logs more potent on a molar basis than butyrate derivatives in triggering leukemic cell maturation.8 However, in human leukemia cells (eg, U937), administration of SAHA above threshold concentrations leads to diminished maturation and a dramatic increase in mitochondrial injury and apoptosis.9 Thus, the response to HDACIs may be both concentration and cell type specific. More recently, the cinnamic acid hydroxamate NVP-LAQ824 has shown impressive antileukemic activity when administered in the low nanomolar range,10 making it a particularly attractive candidate for clinical development. In the case of novel HDACIs like NVP-LAQ824, as well as for HDACIs in general, the specific mechanisms determining whether such agents trigger differentiation vs apoptosis in leukemic cells remains to be fully elucidated. The answer to this question may lie in evolving evidence that HDACIs exert pleiotropic actions that may be distinct from their effects on histone acetylation, including acetylation of non-histone proteins,11 generation of reactive oxygen species,12 inhibition of proteasome function,13 and production of ceramide,14 among numerous others.

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Acknowledgements

This work was supported by awards CA93738, CA63753, and CA100866 from the NIH, DAMD-17-03-1-0209 from the Department of Defense, and award 6045-03 from the Leukemia and Lymphoma Society of America.

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Grant, S. The novel histone deacetylase inhibitor NVP-LAQ824: an addition to the therapeutic armamentarium in leukemia?. Leukemia 18, 1931–1933 (2004). https://doi.org/10.1038/sj.leu.2403522

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