Histone deacetylase inhibitors: Insights into mechanisms of lethality

Roberto R. Rosato, Steven Grant

Research output: Contribution to journalReview article

109 Scopus citations

Abstract

Histone deacetylases (HDACs) have recently emerged as an important target for therapeutic intervention in cancer and potentially other human diseases. By modulating the acetylation status of histones, histone deacetylase inhibitors (HDACIs) alter the transcription of genes involved in cell growth, maturation, survival and apoptosis, among other processes. Early clinical results suggest a potentially useful role for HDACIs in the treatment of certain forms of lymphoma (e.g., cutaneous T cell lymphoma) and acute leukaemia. An unresolved question is how HDACIs induce cell death in tumour cells. Recent studies suggest that acetylation of nonhistone proteins may play an important role in the biological effects of this class of compounds, and may explain lack of correlation between histone acetylation and induction of cell death by HDACIs in some circumstances. Recently, attention has focussed on the effects of HDACIs on disruption of co-repressor complexes, induction of oxidative injury, upregulation of the expression of death receptors, generation of lipid second messengers such as ceramide, interference with the function of chaperone proteins and modulation of the activity of NF-κB as critical determinants of lethality. Aside from providing critical insights into the mechanism of action of HDACIs in neoplastic disease, these findings may provide a foundation for the rational development of combination studies, involving HDACIs in combination with either conventional cytotoxic drugs as well as more novel targeted agents.

Original languageEnglish (US)
Pages (from-to)809-824
Number of pages16
JournalExpert Opinion on Therapeutic Targets
Volume9
Issue number4
DOIs
StatePublished - Aug 1 2005

Keywords

  • Apoptosis
  • Ceramide
  • Epigenetics
  • Extrinsic pathway
  • Heat-shock protein
  • Histone deacetylase inhibitor (HDACI)
  • NF-κB

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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