Histone deacetylase inhibitors open new doors in cancer therapy
Introduction
The accessibility of DNA to proteins such as transcription factors and their co-factors is determined in part by a series of chromatin modifying enzymes. The text book “beads-on-a-string” structure of DNA wrapped around nucleosomes can be further condensed into higher order chromatin, known as heterochromatin and euchromatin, the latter being more transcriptionally active and containing most protein encoding genes [1]. The nucleosome itself is made up of an octamer of histone proteins, two each of H2A, H2B, H3 and H4, with 145 bp of DNA wrapped around it (Fig. 1). Modification of the highly charged lysine residues in the N-terminal histone tail is one mechanism whereby chromatin condensation is controlled. These lysine residues are subject to modification by acetylation and methylation, which are post-translational modifications that have a considerable impact on transcriptional activity [2].
Despite the fact that histone acetylation was shown some years ago [3], the enzymes controlling acetylation have only recently come to light [4], [5], [6]. Histone deacetylases (HDAC) are evolutionarily conserved and expressed in organisms from archaebacteria to man and, together with the conversely acting histone acetyl transferases (HATs), control the acetylation level of chromatin and subsequent transcriptional activity (Fig. 2). HDACs remove the acetyl group from histones using a charge-relay mechanism consisting of two adjacent histidine residues, two aspartate residues and one tyrosine residue, and crucial for this charge-relay system is a Zn2+ ion, which binds deep in the pocket of the enzyme [7]. Inhibitors such as trichostatin A (TSA), SAHA and PXD101, function by displacing the zinc atom [7].
The HDAC family is divided into the Zn-dependent (Class I and Class II) and Zn independent, NAD-dependent (Class III) enzymes (Table 1). The Zn-dependent enzymes have been the focus of intense research, whilst the Sir2 (silent information regulator) family recently have been implicated in acetylation and regulation of key cell cycle proteins such as p53 [8]. The HDAC inhibitors described here are inhibitors of Class I and Class II enzymes. To date, eleven HDAC family members in Classes I and II have been characterised; HDACs 1, 2, 3, 8 are Class I and HDACs 4, to 7, 9 and 10 are Class II, a grouping based on sequence similarity [9]. The most recently identified member, HDAC 11, is most likely Class I, although the similarity is weak.
Ultimately, the expression and activity profile of each family member in normal relative to diseased tissue, or tissue-specific profiles, will be crucial information in the design of new therapeutic strategies. Important questions such as those relating to which family member to target for improved efficacy or reduced toxicity have yet to be addressed. Notably, the current HDAC inhibitors in clinical trials are generally regarded as pan HDAC inhibitors, on the basis of structural modeling, although with the caveat that robust enzyme assays that measure the activity of each family member have not yet been established. Against this background, a number of recent studies have allowed us to gain information about some aspects of the tissue-specific expression of HDACs; for example, HDAC 9 in heart, HDAC 7 in T cells, and HDAC 6 in breast [9], [10], [11]. In general, however, the expression of HDAC enzymes is fairly ubiquitous [9].
Section snippets
Chemistry strategies for the design of novel HDAC
The naturally occurring anti-fungal antibiotic TSA was one of the first HDAC inhibitors identified as an anti-proliferative agent, and although it has never progressed as a clinical candidate, has been an invaluable tool in validating HDAC enzymes as potential anti-cancer targets. TSA is a hydroxamic acid-based compound which fits into the HDAC active site, chelating the Zn2+ ion and inhibiting the enzyme at a low nM IC50. Subsequent hydroxamic acid-based HDAC inhibitors, including SAHA, PXD101
Mechanism of action of HDAC inhibitors
There is a large body of literature which indicates that HDAC inhibitors block the cell cycle and induce apoptosis or differentiation depending on the cell-type and environmental factors [21], [22], [23], [24]. It is consistent with the cell cycle arrest that SAHA regulates cell cycle control proteins, such as p21, p27, and gelsolin [25]. Whilst this may result from a transcriptional effect on the relevant target genes (Fig. 2), the activity of other proteins such as E2F, pRb, and p53 is
Clinical utility of HDAC inhibitors
An important finding in predicting the potential utility of HDAC inhibitors in the clinic is their activity in cell-lines that are resistant to existing chemotherapeutics. For example, Gleevec-resistant Bcr/Abl human chromic myelogenous leukaemia (CML) cells are sensitised to Gleevec upon co-treatment with SAHA [32]. In addition, CD34-positive progenitor cells from patients with Gleevec refractory CML respond to SAHA treatment and exhibit increased apoptosis and histone acetylation levels [33].
Future development of HDAC inhibitors
The first generation of HDAC inhibitors in clinical trials (Table 2) have shown encouraging anti-tumour effects, with well-tolerated safety profiles. None of the agents in clinical trials have been developed to selectively target individual HDAC family members. Consequently, these agents are generally viewed as pan-HDAC inhibitors, although future experiments are required to substantiate this view. Nevertheless, there is considerable interest in developing molecules with selectivity towards
Conclusions
Chromatin modifying enzymes have provided a number of important and increasingly validated therapeutic targets for oncology. There is now compelling evidence from the number of HDAC inhibitors in clinical studies that these molecules exhibit efficacy in human disease. It is the hope that their application, most probably in combination with chemotherapeutics, will lead to broad clinical utility in many tumour types. We can confidently anticipate that this field will continue to expand as
Acknowledgements
We thank Marie Caldwell for help in preparation of the manuscript. We are grateful to the MRC for supporting our laboratory.
References (46)
- et al.
Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy
Cell
(2002) - et al.
Weinstein, HDAC7, a thymus-specific Class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis
Immunity
(2003) - et al.
Broad spectrum antiprotozoal agents that inhibit histone deacetylase: structure-activity relationships of apicidin
Bioorg. Med. Chem. Lett.
(2001) - et al.
The cell cycle, chromatin and cancer: mechanism based therapeutics come of age
Drug Disc Today
(2003) - et al.
Transcriptional activation of p21WAF1/CIP1 by Apicidin, a novel histone deacetylase inhibitor
Biochem. Biophys. Res. Commun.
(2001) - et al.
Activation of p53 sequence specific DNA binding by acetylation of the p53 C-terminal domain
Cell
(1997) - et al.
Co-treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances Gleevec-induced apoptosis of Bcr-Abl positive human acute leukemia cells
Blood
(2003) - et al.
Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7
J. Biol. Chem.
(2001) - et al.
The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress
Cell
(2003) A model for chromatin structure
Nucl. Acid Res.
(1975)
Translating the histone code
Science
RNA synthesis and histone acetylation during the course of gene activation in lymphocytes
Proc. Natl. Acad. Sci.
A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p
Science
The SIR 2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability
Gen. Dev.
Isolation and mapping of a human gene (PRD3L1) that is homologous to PRD3, a transcription factor in Saccharomyces cerevisiae
Cytogenet Cell Genet.
Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors
Nature
Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice
Proc. Natl. Acad. Sci.
Histone deacetylases (HDACs): characterization of the classical HDAC family
Biochem. J.
Phase I clinical trial of histone deacetylase inhibitors: suberoylanilide hydroxamic acid administered intravenously
Clin. Can. Res.
Brown, pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101
Mol. Cancer Theor.
Valproate and valproate-analogues: potent tools to fight against cancer
Curr. Med. Chem.
Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms
Clin. Cancer Res.
A phase I trial of depsipeptide (FR901228) in patients with advanced cancer
J. Exp. Theor. Oncol.
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