Histone Deacetylase Inhibitors

https://doi.org/10.1016/S0065-230X(04)91004-4Get rights and content

Abstract

The base sequence of DNA provides the genetic code for proteins. The regulation of expression or suppression of gene transcription is largely determined by the structure of the chromatin—referred to as epigenetic gene regulation (Agalioti et al., 2002; Jenuwein and Allis, 2001; Richards and Elgin, 2002; Spotswood and Turner, 2002; Zhang and Reinberg, 2001). Posttranslational modifications of the histones of chromatin play an important role in regulating gene expression. Some of the most extensively studied epigenetic modifications involve acetylation⧸deacetylation of lysines in the tails of the core histones, which is controlled by the action of histone deacetylases (HDACs) and histone acetyltransferases (HATs). A controlled balance between histone acetylation and deacetylation appears to be essential for normal cell growth (Waterborg, 2002). Alterations in the structure or expression of HATs and HDACs occur in many cancers (Jones and Baylin, 2002; Marks et al., 2001, 2003; Timmermann et al., 2001; Wang et al., 2001). A structurally diverse group of molecules has been developed that can inhibit HDACs (HDACi) (Arts et al., 2003; Bouchain and Delorme, 2003; Curtin and Glaser, 2003; Johnstone and Licht, 2003; Marks et al., 2003; Remiszewski, 2003; Richon et al., 1998; Yoshida et al., 2003). These inhibitors induce growth arrest, differentiation, and⧸or apoptosis of cancer cells in vitro and in in vivo tumor-bearing animal models. Clinical trials with several of these agents have shown that certain HDACi have antitumor activity against various cancers at doses that are well tolerated by patients (Gottlicher et al., 2001; Kelly et al., 2002a,b; Piekarz et al., 2001; Wozniak et al., 1999).

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.

  1. 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

References (136)

  • S.G. Gray et al.

    The human histone deacetylase family

    Exp. Cell Res.

    (2001)
  • R.W. Johnstone et al.

    Histone deacetylase inhibitors in cancer therapy: Is transcription the primary target?

    Cancer Cell

    (2003)
  • S. Khochbin et al.

    Functional significance of histone deacetylase diversity

    Curr. Opin. Genet. Dev.

    (2001)
  • M. Lachner et al.

    The many faces of histone lysine methylation

    Curr. Opin. Cell Biol.

    (2002)
  • H. Lehrmann et al.

    Histone acetyltransferases and deacetylases in the control of cell proliferation and differentiation

    Adv. Cancer Res.

    (2002)
  • P.A. Marks et al.

    Histone deacetylases

    Curr. Opin. Pharmacol.

    (2003)
  • T.A. McKinsey et al.

    Control of muscle development by dueling HATs and HDACs

    Curr. Opin. Genet. Dev.

    (2001)
  • T.A. McKinsey et al.

    Signaling chromatin to make muscle

    Curr. Opin. Cell Biol.

    (2002)
  • P. Neumeister et al.

    Senescence and epigenetic dysregulation in cancer

    Int. J. Biochem. Cell. Biol.

    (2002)
  • K. Petrie et al.

    The histone deacetylase 9 gene encodes multiple protein isoforms

    J. Biol. Chem.

    (2003)
  • C.J. Phiel et al.

    Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen

    J. Biol. Chem.

    (2001)
  • A. Reddy et al.

    Using cancer genetics to guide the selection of anticancer drug targets

    Curr. Opin. Pharmacol.

    (2002)
  • E.J. Richards et al.

    Epigenetic codes for heterochromatin formation and silencing: Rounding up the usual suspects

    Cell

    (2002)
  • A. Ardizzoni et al.

    Histone deacetylation inhibitors

    Suppl. Tumori

    (2002)
  • J. Arts et al.

    Histone deacetylase inhibitors: From chromatin remodeling to experimental cancer therapeutics

    Curr. Med. Chem.

    (2003)
  • A.J. Boivin et al.

    Antineoplastic action of 5-aza-2′-deoxycytidine and phenylbutyrate on human lung carcinoma cells

    Anticancer Drugs

    (2002)
  • G. Bouchain et al.

    Novel hydroxamate and anilide derivatives as potent histone deacetylase inhibitors: Synthesis and antiproliferative evaluation

    Curr. Med. Chem.

    (2003)
  • L.M. Butler et al.

    Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo

    Cancer Res.

    (2000)
  • L.M. Butler et al.

    Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase

    Clin. Cancer Res.

    (2001)
  • L.M. Butler et al.

    The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin

    Proc. Natl. Acad. Sci. USA

    (2002)
  • M. Carducci et al.

    Phenylbutyrate (PB) for refractory solid tumors: Phase I clinical and pharmacologic evaluation of intravenous and oral PB

    Anticancer Res.

    (1997)
  • M.A. Carducci et al.

    Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate

    Clin. Cancer Res.

    (1996)
  • H.M. Chan et al.

    Acetylation control of the retinoblastoma tumour-suppressor protein

    Nat. Cell Biol.

    (2001)
  • S.M. Chang et al.

    Phase II study of phenylacetate in patients with recurrent malignant glioma: A North American Brain Tumor Consortium report

    J. Clin. Oncol.

    (1999)
  • J.H. Choi et al.

    Expression profile of histone deacetylase 1 in gastric cancer tissues

    Jpn. J. Cancer Res.

    (2001)
  • D.C. Coffey et al.

    The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans-retinoic acid

    Cancer Res.

    (2001)
  • W.D. Cress et al.

    Histone deacetylases, transcriptional control, and cancer

    J. Cell. Physiol.

    (2000)
  • M. Curtin et al.

    Histone deacetylase inhibitors: The Abbott experience

    Curr. Med. Chem.

    (2003)
  • M.P. Czubryt et al.

    Regulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and mitochondrial function by MEF2 and HDAC5

    Proc. Natl. Acad. Sci. USA

    (2003)
  • C.F. Deroanne et al.

    Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling

    Oncogene

    (2002)
  • A.J. de Ruijter et al.

    Histone deacetylases (HDACs): Characterization of the classical HDAC family

    Biochem. J.

    (2003)
  • M. Duvic et al.

    Phase II trial of oral suberoylanilide hydroxamic acid (SAHA) for cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma

  • R. Fenrick et al.

    Role of histone deacetylases in acute leukemia

    J. Cell. Biochem. Suppl.

    (1998)
  • M.S. Finnin et al.

    Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors

    Nature

    (1999)
  • W. Fischle et al.

    Binary switches and modification cassettes in histone biology and beyond

    Nature

    (2003)
  • R. Furumai et al.

    Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin

    Proc. Natl. Acad. Sci. USA

    (2001)
  • R. Furumai et al.

    FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases

    Cancer Res.

    (2002)
  • S.A. Gayther et al.

    Mutations truncating the EP300 acetylase in human cancers

    Nat. Genet.

    (2000)
  • J. Gilbert et al.

    A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies

    Clin. Cancer Res.

    (2001)
  • J. Gilbert et al.

    Methyltransferase (MT) activity and gene expression in tumor biopsies from patients enrolled in a phase I study of the MT inhibitor, 5-azacytidine and histone deacetylase inhibitor, phenylbutyrate in refractory solid tumors

    Proc. Am. Soc. Clin. Oncol.

    (2001)
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