Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Abstract

Histone deacetylase (HDAC) and histone acetyltransferase (HAT) are enzymes that influence transcription by selectively deacetylating or acetylating the eta-amino groups of lysines located near the amino termini of core histone proteins. It is well-established that in transcriptionally active chromatin, histones generally are hyperacetylated and, conversely, hypoacetylated histones are coincident with silenced chromatin. Revived interest in these enzymatic pathways and how they modulate eukaryotic transcription has led to the identification of multiple cofactors whose complex interplay with HDAC affects gene expression. Concurrent with these discoveries, screening of natural product sources yielded new small molecules that were subsequently identified as potent inhibitors of HDAC. While predominantly identified using antiproliferative assays, the biological activity of these new HDAC inhibitors also encompasses significant antiprotozoal, antifungal, phytotoxic and antiviral applications. These newly discovered HDAC inhibitors served as lead structures for the development of improved derivatives including related reagents with considerable potential as tools to further elucidate the mechanism of transcriptional regulation.

The transcription machinery and the molecular toolbox to control gene expression in Toxoplasma gondii and other protozoan parasites

“…Yeast GCN5 is a subunit of two high molecular mass histone acetylase complexes that are recruited to the promoter by interaction with transcription factors (for a review see [26]). Interestingly drugs that inhibit histone deacetylases, such as apicidin, show a strong antiprotozoal activity, suggesting that a fine-tuning between histone acetylation and deacetylation is important for the survival of the parasite [27,28]. In this context, recent studies have revealed several hints that chromatin remodelling plays a role in regulation of antigenic variation in P. falciparum.…”

Sodium butyrate restores ASC expression and induces apoptosis in LS174T cells

“…SCFAs induce cell cycle arrest, differentiation and apoptosis in cancer cells, several also have anti-inflammatory activities, and a number have progressed to clinical trials. These agents, which include NaBu and (R)-trichostatin A (TSA), have displayed anti-proliferative and differentiating activity in a wide variety of cancers (7)(8)(9). Research has shown that NaBu induces tumor cell apoptosis in colon, breast, esophageal and prostate cancer (10).…”

Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents

“…The dynamic balance of DNA acetylation levels in cells, modulated by histone deacetylase (HDAC) and histone acetyltransferases (HATs), is crucial for regulating chromatin structure and transcriptional dysregulation of genes that are implicated in controlling either cell cycle progression or pathways regulating cell differentiation and/or apoptosis (1)(2)(3)(4)(5). Evidence has shown that this epigenetic marking system is associated with inappropriate gene expression in many forms of cancer (3,6,7).…”

“…Evidence has shown that this epigenetic marking system is associated with inappropriate gene expression in many forms of cancer (3,6,7). Encouraged by the finding that inhibition of HDAC induces cancer cell apoptosis (8,9), inhibitors of HDAC have been developed as a potent and specific strategy for the treatment of solid tumors and hematological malignancies (1,2,(10)(11)(12). Several classes of HDAC inhibitors have been developed including short-chain fatty acids, such as phenylbutyrate and valproic acid (10); various hydroxamic acid derivatives such, as SAHA and TSA (4,12,13); and cyclic tetrapeptides, such as depsipeptide (2,10,14).…”