Histone Deacetylase Inhibitors

Acetylation of DNA-associated histones is linked to activation of gene transcription, whereas histone deacetylation is associated with transcriptional repression. Acute promyelocytic leukemia (APL) provides an excellent model to illustrate the modulation of gene transcription by acetylation and the therapeutic potential of histone deacetylase inhibitors. APL is a hematopoietic cancer that involves the retinoic acid receptor a (RARa) gene that maps to the long arm of chromosome 17q21. Ninety-five percent of APL cases arise from a translocation between chromosomes 15 and 17 (t15:17.q21), which leads to the formation of the fusion protein PML-RARa. PML-RARa results in a transcriptional block of the normal granulocytic differentiation pathway. RARa is a member of the nuclear hormone receptor family that acts as a ligand-inducible transcriptional activation factor by binding to retinoic acid response elements (RAREs) in a heterodimer with RXR, a related family of nuclear receptors. In the presence of a ligand (all-frans-retinoic acid), the complex promotes transcription of retinoic acid-responsive genes. In the absence of ligand, transcription is silenced by a multistep process involving recruitment of transcriptional regulators, corepres-sors, and nuclear receptor core repressors such as Sin3 to form a complex. Sin3, in turn, recruits a histone deacetylase that causes condensation of chromatin and prevents accessibility of transcriptional machinery to target genes. The presence of a ligand (all-frans-retinoic acid) induces a conformational change in RAR enabling the dissociation of the repressor complex and recruitment of coactiva-tors (such as the family members). The coactivator molecules possess intrinsic histone acetylase activity that causes unwinding of DNA thereby facilitating transcription and promoting granulocyte differentiation. In an APL patient with a transcriptional block and refractoriness to all-frans-retinoic acid resulting in a highly resistant form of APL, Warrell and colleagues showed that treatment with sodium butyrate, a histone deacetylase inhibitor, restored sensitivity to the antileukemic effects of all-frans-retinoic acid.129

Evaluation of sodium phenyl butyrate (buphenyl) has demonstrated its beneficial effect in the treatment of other disorders including the hemoglobinopathy, p-thalessemia, in acute myelogenous leukemia and in prostate cancer. Phenyl butyrate is one of the older generation of histone deacetylase inhibitors and presently additional inhibitors are being tested in clinical trials.132 Among these, the inhibitory agent suberoylanilide hydroxamic acid has shown differentiating effects in a bladder cancer cell line. Depsipeptide isolated from Chrombacfer/wm v/olacewm has been demonstrated to have potent cytotoxic activity through several different mechanisms including histone deacetylase inhibition. This agent demonstrated activity against chronic myelogenous leukemia cells resulting in acetylation of histone H3 and H4 as well as expression of apoptotic proteins involving caspase pathways.132

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