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Histone deacetylase inhibitors in cancer treatment
David M Vigushin1, R Charles Coombes
1Department of Cancer Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital Campus, London W12 0NN, UK. d.vigushin@ic.ac.uk
Abstract:
Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anticancer agents for the treatment of solid and hematological malignancies. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that inhibit proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models. HDAC inhibition causes acetylated nuclear histones to accumulate in both tumor and normal tissues, providing a surrogate marker for the biological activity of HDAC inhibitors in vivo. The effects of HDAC inhibitors on gene expression are highly selective, leading to transcriptional activation of certain genes such as the cyclin-dependent kinase inhibitor p21WAF1/CIP1 but repression of others. HDAC inhibition not only results in acetylation of histones but also transcription factors such as p53, GATA-1 and estrogen receptor-alpha. The functional significance of acetylation of non-histone proteins and the precise mechanisms whereby HDAC inhibitors induce tumor cell growth arrest, differentiation and/or apoptosis are currently the focus of intensive research. Several HDAC inhibitors have shown impressive antitumor activity in vivo with remarkably little toxicity in preclinical studies and are currently in phase I clinical trial. The focus of this review is the development and clinical application of HDAC inhibitors for the treatment of cancer.
Insights
Histone deacetylase (HDAC) inhibitors show promise as anticancer agents by inhibiting tumor cell growth and inducing differentiation. These compounds, currently in clinical trials, offer a novel therapeutic strategy with minimal toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents.
- Numerous structurally diverse HDAC inhibitors have been identified with potent anti-tumor effects in preclinical models.
- HDAC inhibition leads to histone acetylation, serving as a biomarker for drug activity.
Purpose of the Study:
- To review the development and clinical applications of HDAC inhibitors in cancer treatment.
- To highlight the mechanisms of action, including effects on gene expression and protein acetylation.
- To discuss the therapeutic potential and ongoing clinical investigations of HDAC inhibitors.
Main Methods:
- Review of preclinical and clinical studies on HDAC inhibitors.
- Analysis of molecular mechanisms underlying HDAC inhibition, including effects on histone and non-histone protein acetylation.
- Evaluation of antitumor activity and toxicity profiles in various cancer models.
Main Results:
- HDAC inhibitors demonstrate significant antitumor activity, inhibiting proliferation and inducing differentiation or apoptosis in tumor cells.
- HDAC inhibition selectively alters gene expression, activating genes like p21WAF1/CIP1 and repressing others.
- Acetylation of non-histone proteins, including transcription factors like p53, is a key effect of HDAC inhibitors.
Conclusions:
- HDAC inhibitors are a promising new therapeutic strategy for solid and hematological malignancies.
- Further research is ongoing to elucidate the precise mechanisms and optimize clinical applications.
- Several HDAC inhibitors are progressing through Phase I clinical trials, showing encouraging antitumor activity with low toxicity.