Histone Deacetylase Inhibitors
Section snippets
Chromatin Structure
Chromatin is structurally complex, consisting of DNA, histones, and nonhistone proteins (Jenuwein 2001, Lachner 2002, Luger 1997, Spotswood 2002, Wolffe 1996, Zhang 2001). Nucleosomes are repeating units in chromatin composed of approximately 146 base pairs of two superhelical turns of DNA wrapped around an octamer core of pairs of histones H4, H3, H2A, and H2B (Luger 1997, Wolffe 1996). The amino-terminal tails of the histones are subject to posttranslational modification by acetylation of
Histone Deacetylases and Histone Acetyltransferases
There are three classes of mammalian HDAC enzymes (de Ruijter 2003, Khochbin 2001, Marks 2003). Class I includes HDACs 1, 2, 3, and 8; these are related to yeast RPD3 deacetylase, have molecular masses of 22–55 kDa, and share homology in their catalytic sites (Table I). Class II deacetylases include HDACs 4, 5, 6, 7, 9, and 10, are larger molecules with molecular masses between 120 and 135 kDa, and are related to yeast HDA1 deacetylase. HDAC 6 contains two catalytic domains (Hubbert 2002,
Histone Deacetylases⧸Histone Acetyltransferases and Human Cancers
Disruption of HAT or HDAC activity has been found in many human cancers (Choi 2001, Fenrick 1998, Gayther 2000, Giles 1998, He 2001, Jones 2002, Kawai 2003, Lehrmann 2002, Marks 2001, Murata 2001, Neumeister 2002, Smirnov 2000, Timmermann 2001, Toh 2003, Wang 1998, Wang 2001). Genes that encode HAT enzymes are translocated, amplified, overexpressed, and⧸or mutated in various cancers—both hematological and epithelial. Two closely related HATs, CBP and p300, are altered in some tumors by either
Histone Deacetylase Inhibitors
HDAC inhibitors (Table II) reported to date can be divided into several structural classes including hydroxamates, cyclic peptides, aliphatic acids, and benzamides (Miller et al., 2003). TSA (Yoshida et al., 1990) was the first natural product hydroxamate discovered to inhibit HDACs directly. SAHA, which contains relatively less structural complexity, was found to be a nanomolar inhibitor of partially purified HDAC, as was pyroxamide (Richon 1996, Richon 1998). m-Carboxycinnamic acid
Effect on Gene Expression
The mechanism of the antiproliferative effects of HDAC inhibitors involves, at least in part, altering the expression of genes either by directly affecting chromatin structure by causing an accumulation of acetylated histones, or by affecting the activity of transcription factors by increasing the acetylation state of the transcription factors (Fig. 1).
The HDAC inhibitor-induced increase in the state of acetylation of histones and transcription factors leads to both the increased and decreased
Clinical Trials with Histone Deacetylase Inhibitors
A number of HDAC inhibitors have entered into phase I⧸II clinical trials (Table V). Although several of these inhibitors are showing encouraging results, phenylacetate is the only approved agent for use in patients. Phenylacetate has been approved for use in children with urea cycle disorders and additionally in patients with portal encephalopathy and chemotherapy-induced hyperammonemia. In patients with advanced malignant diseases, clinical trials of phenylacetate have shown modest palliative
Conclusions and Perspectives
HDAC inhibitors are promising new targeted anticancer agents. HDAC inhibitors cause cancer cell growth arrest, differentiation, and⧸or apoptosis both in vitro and in vivo of a broad spectrum of malignant cells. Normal cells are much less sensitive to HDAC inhibitors than are transformed cells.
• We need to pursue a better understanding of the basis of the selectivity of HDAC inhibitors in altering transcription of genes: why are normal cells so relatively resistant to inhibitors compared with
Acknowledgements
The studies reviewed in this article representing research in the authors' laboratories were supported, in part, by grants from the National Cancer Institute (CA-0974823), the Robert J. & Helen C. Kleberg Foundation, the DeWitt Wallace Fund for the Memorial Sloan-Kettering Cancer Center, the Susan and Jack Rudin Foundation, and the David H. Koch Prostate Cancer Research Award. Memorial Sloan-Kettering Cancer Center and Columbia University jointly hold patents on hydroxamic acid-based polar
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