Creating zinc monkey wrenches in the treatment of epigenetic disorders

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The approval of suberoylanilide hydroxamic acid by the FDA for the treatment of cutaneous T-cell lymphoma in October, 2006 sparked a dramatic increase in the development of inhibitors for the class of enzymes known as the histone deacetylases (HDACs). In recent years, a large number of combination therapies involving histone deacetylase inhibitors (HDACIs) have been developed for the treatment of a variety of malignancies and neurodegenerative disorders. Promising evidence has been reported for the treatment of pancreatic cancer, prostate cancer, and leukemia as well as a number of other previously difficult to treat cancers. Drug combination approaches have also shown promise for the treatment of mood disorders including bipolar disorder and depression. In addition to these drug combination approaches, HDACIs alone have demonstrated effectiveness in the treatment of Parkinson's disease, Alzheimer's disease, Rubinstein–Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease, multiple sclerosis, anxiety, and schizophrenia. Adverse inflammatory affects observed with traumatic brain injury and arthritis have also been alleviated by treatment with certain HDACIs. Based on the diverse utility and wide range of mechanistic actions observed with this class of drugs, the future development of better drug combination therapies and more selective HDACIs is warranted.

Introduction

The synthesis of suberoylanilide hydroxamic acid (SAHA) in 1996 and the subsequent identification of its biological target, a class of enzymes known as the histone deacetylases (HDACs), gave rise to a novel class of therapeutic agents, the HDAC inhibitors (HDACIs) [1, 2]. On October 6th, 2006, after nearly six years of clinical trials, the FDA approved the use of SAHA for the treatment of cutaneous T-cell lymphoma (CTCL) which provided the scientific community with a testament as to the legitimacy of this new class of drugs [3]. HDACs, along with their counterpart, histone acetyl transferases (HATs), are involved in the regulation of gene expression via deacetylation/acetylation of the N-terminal lysine residues of nuclear histones (Figure 1). HDACs and HATs have also been shown to have a variety of nonhistone substrates including p53, HSP90, α-tubulin, and HMGB1 that are related to gene expression, cell proliferation, and apoptosis [4]. The HDACIs have shown promising results for use in the treatment of a wide variety of disease states including certain neurodegenerative disorders, a wide range of malignancies, and even adverse inflammatory responses [5, 6, 7]. Current research regarding the therapeutic uses of the HDACIs has been centered on combination therapies and the synergistic effects of using HDACIs with other known drugs (Table 1). The focus of this review will be to highlight the advances in HDAC research over the past two years and to discuss potential future directions of this research area. Structures of HDACIs referenced in this review can be found in Figure 2.

Section snippets

Combination therapy for various malignancies

One of the most frequently reported HDAC combination therapies is the use of an HDACI in conjunction with a DNA methyltransferase inhibitor (DNMTI) [8, 9, 10, 11, 12]. A recent study has shown that treatment of glioma cells with valproic acid (VPA), a low potency pan-selective HDACI, and 5-aza-2′-deoxycytidine (5Aza-dC), a DNMTI, was able to induce the expression of NY-ESO-1 in cancerous cells. NY-ESO-1, under normal conditions, is only expressed in certain reproductive tissues which lack the

Cancer

In addition to the use of HDACIs in combination with other drugs, these inhibitors have shown promise individually for the treatment of cancer, neurodegenerative disorders, and inflammation. A series of potent and selective phenylthiazole compounds were shown to have low nanomolar potency against pancreatic cancer cells in vitro [22]. Another series of triazolylphenyl-based HDACIs also exhibited low nanomolar potency against a set of five pancreatic cancer cell lines [23]. A novel

Selective HDACIs

A large portion of HDAC research has been dedicated to the discovery of selective HDACIs [51]. Selective HDACIs would theoretically allow the reduction of unwanted side effects exhibited by pan-HDACIs as well as the determination of the biological functions related to each HDAC isoform [52, 53]. Selectivity between class I and class II HDACs has been achieved by a variety of research groups. Recent examples of class I selective HDACIs include ampicidin-derived ketones, nonpeptide macrocycles,

Conclusion

In addition to the development of isoform specific HDACIs, future directions of HDAC research include further investigation into dual drug therapies as well as investigation of the apoptotic pathways selectively induced by HDACIs in transformed cells. Synergistic effects exhibited by the HDACIs and other known drugs may allow for the treatment of various disease states with submaximal doses which could possibly reduce the occurrence of unwanted side effects. Improved understanding of the

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