Elsevier

Biochemical Pharmacology

Volume 68, Issue 6, 15 September 2004, Pages 1139-1144
Biochemical Pharmacology

Histone deacetylase inhibitors open new doors in cancer therapy

https://doi.org/10.1016/j.bcp.2004.05.034Get rights and content

Abstract

Cancer drug development has moved from conventional cytotoxic chemotherapeutics to a more mechanism-based targeted approach towards the common goal of tumour growth arrest. The rapid progress in chromatin research has supplied a plethora of potential targets for intervention in cancer. Here, we focus on the histone deacetylase (HDAC) inhibitors, together with their current status of clinical development and potential utility in cancer therapy. HDACs have been widely implicated in growth and transcriptional control, and inhibition of HDAC activity using small molecules causes apoptosis in tumour cells. We discuss the rationale for the development of HDAC inhibitors as novel anti-cancer agents, the potential clinical application and explore ideas on how we may move towards patient stratification with the possibility of increasing efficacy in the clinic.

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.

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    Present address: BTG plc, 10 Fleet Street, Limeburner Lane, London EC4M 7SB, UK.

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