Elsevier

Drug Discovery Today

Volume 10, Issue 3, 1 February 2005, Pages 197-204
Drug Discovery Today

Review
Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases?

https://doi.org/10.1016/S1359-6446(04)03309-4Get rights and content

Abstract

Histone deacetylase (HDAC) inhibitors induce cell cycle arrest and differentiation in cancer cells and have been in Phase I-II clinical trials for the treatment of various solid or haematological malignancies. In recent years, HDAC inhibitors have emerged as potent contenders for anti-inflammatory drugs, offering new lines of therapeutic intervention for rheumatoid arthritis or lupus erythematosus. The molecular mode of action of HDAC inhibitors is still controversial but seems to rely on reduced inflammatory mediator production, such as nitric oxide or cytokines, which implies inhibition of the transcription factor NF-ĪŗB. These anti-inflammatory effects will hopefully lead us to appreciate the complex anti-tumour effects of HDAC inhibitors.

Section snippets

HDAC inhibitors

Mammalian HDACs have been classified into three classes [7, 17, 18]. Class I HDACs (HDACs 1, 2, 3 and 8) are homologues of yeast RPD3 and are found exclusively in the nucleus. Class II HDACs (HDACs 4, 5, 6, 7, 9 and 10), homologues of yeast Hda1, are found in both the nucleus and the cytoplasm. HDAC11 has properties of both class I and class II HDACs. Class III HDACs (Sirt1-Sirt7) are homologues of yeast Sir2 and form a structurally distinct class of NAD-dependent enzymes [7, 17, 18]. Northern

HDAC inhibitors, cytokine and NO expression and inflammatory diseases

Recent results have indicated that HDAC inhibitors can reduce the cytokine and NO production that contribute to various inflammatory diseases [15, 26, 27, 28]. Thus, the observation that butyrate and TSA inhibit IL-8 expression in colonic epithelial cells suggested that HDAC inhibitors can be used for the effective treatment of ulcerative colitis through increased histone acetylation and reduced production of pro-inflammatory cytokines by the intestinal epithelium (Table 1) [14, 15, 26].

HDAC inhibitors and transcription factors

Several results have demonstrated inhibition of NF-ĪŗB transcriptional activity after treatment with HDAC inhibitors. As initially reported, this transcription factor is crucial for the expression of numerous pro-inflammatory mediators, such as inducible NO synthase (iNOS), IL-6, IL-8, IL-10 and IL-12 [29, 34, 36]. Moreover, other anti-inflammatory drugs, such as salicylates and glucocorticoids, are also known to inhibit NF-ĪŗB [1]. However, and as discussed in a subsequent section, activation of

HDAC inhibitors, inflammation and cancer: an example of osteo-articular diseases

Here, osteo-articular tissue will be used as an example to discuss how inhibition of inflammation and bone resorption by HDAC inhibitors could help explain their anti-tumour activities. However, this hypothesis, which could be extended to other tissues and malignancies, needs additional evaluation in animal models and human clinical trials.

Primary or metastatic bone tumours favour inflammation and osteoclast-mediated bone resorption. The candidates for osteolytic mediators are vitamins (VitD3),

Contraindications in inflammatory diseases

In contrast to these anti-inflammatory effects, TSA and SAHA have been shown to strongly potentiate microglial inflammation. These HDAC inhibitors enhanced the LPS-induced expression of IL-6, TNF-Ī±, macrophage inflammatory protein-2 and NO in primary microglial cells as well as in neural co-cultures (Table 1) [50]. Therefore, histone acetylation could participate in the inflammatory response associated with a variety of neurodegenerative diseases, stroke and traumatic brain injuries. Whether

New HDAC inhibitors

Based on their various sub-cellular localization, intra-tissue variation and non-redundant activity, the different HDACs are certainly implicated in various specific cellular processes, such as proliferation, metabolism and differentiation. For example, class I HDACs are mainly nuclear enzymes, whereas class II HDACs localize either to the cell nucleus or to the cytoplasm, depending on their phosphorylation and subsequent binding of 14-3-3 proteins.

Moreover, class II HDACs display a

Conclusions and perspectives

Butyrate improves the efficacy of conventional anti-inflammatory treatments in refractory ulcerative colitis [31], therefore, future trials will certainly analyse association of salicylates, glucocorticoids and/or anti-cytokine immunotherapy with low dose HDAC inhibitors for the treatment for other inflammatory diseases. Whether the administration of HDAC inhibitors should be local or systemic will certainly depend on the nature of the inflammatory disease, on the extent of inflammation and its

Acknowledgements

We thank Kanji Mori for critical comments on this manuscript and acknowledge support from the RĆ©gion des Pays de Loire, the Association de Recherche sur le Cancer (ARC), INSERM (Contrat de Recherche StratĆ©gique nĀ°4CR06F), the MinistĆØre de la Recherche (ACI nĀ°TS/0220044) and the ComitĆ© des Pays de Loire de la Ligue Contre le Cancer, France.

References (62)

  • H. Nakajima

    FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor

    Exp. Cell Res.

    (1998)
  • C. Diakos

    Novel mode of interference with nuclear factor of activated T-cells regulation in T-cells by the bacterial metabolite n-butyrate

    J. Biol. Chem.

    (2002)
  • M.A. Wilson

    The histone deacetylase inhibitor trichostatin A blocks progesterone receptor-mediated transactivation of the mouse mammary tumor virus promoter in vivo.

    J. Biol. Chem.

    (2002)
  • M.M. Rahman

    Two histone deacetylase inhibitors, trichostatin A and sodium butyrate, suppress differentiation into osteoclasts but not into macrophages

    Blood

    (2003)
  • Y. Koyama

    Histone deacetylase inhibitors suppress IL-2-mediated gene expression prior to induction of apoptosis

    Blood

    (2000)
  • Y.L. Chung

    A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis

    Mol. Ther.

    (2003)
  • K. Iwata

    Trichostatin A, a histone deacetylase inhibitor, down-regulates interleukin-12 transcription in SV-40-transformed lung epithelial cells

    Cell. Immunol

    (2002)
  • I. Rahman

    Oxidative stress, transcription factors and chromatin remodelling in lung inflammation

    Biochem. Pharmacol

    (2002)
  • F. Miao

    In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions

    J. Biol. Chem.

    (2004)
  • H. Zhong

    The phosphorylation status of nuclear NF-kappa B determines its association with CBP/p300 or HDAC-1

    Mol. Cell

    (2002)
  • Y. Sasakawa

    Antitumor efficacy of FK228, a novel histone deacetylase inhibitor, depends on the effect on expression of angiogenesis factors

    Biochem. Pharmacol

    (2003)
  • F. D'Acquisto

    Inhibition of nuclear factor kappa B (NF-kB): an emerging theme in anti-inflammatory therapies

    Mol. Interv.

    (2002)
  • J. Zlatanova

    Chromatin structure revisited

    Crit. Rev. Eukaryot. Gene Expr.

    (1999)
  • T.K. Archer

    Transcription factor loading on the MMTV promoter: a bimodal mechanism for promoter activation

    Science

    (1992)
  • K.B. Glaser

    Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines

    Mol. Cancer Ther.

    (2003)
  • A.J. de Ruijter

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

    Biochem. J.

    (2003)
  • U.H. Weidle et al.

    Inhibition of histone deacetylases: a new strategy to target epigenetic modifications for anticancer treatment

    Anticancer Res.

    (2000)
  • W.K. Kelly

    Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously

    Clin. Cancer Res.

    (2003)
  • S.Y. Archer

    p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • R. Jaenisch et al.

    Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals

    Nat. Genet.

    (2003)
  • Cited by (0)

    View full text