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Inhibitors of histone deacetylase as new anticancer agents
1Department of Pharmaceutical Chemistry, Westfälische Wilhelms-Universität Münster, Hittorfstr. 58-62, 48149 Münster, Germany. jungm@uni-muenster.de
Abstract:
Inhibitors of histone deacetylase (HDAC) are an emerging class of anticancer agents. They induce hyperacetylation in chromatin usually resulting in activation of certain genes. They induce terminal cell differentiation and/or apoptosis in cancer cells. Histone deacetylase activity is recruited by co-repressor proteins to certain regions of the chromatin and aberrant histone acetylation caused by that recruitment is responsible for the pathogenesis of certain cancers on a molecular level. Inhibitors of HDAC have been identified in natural sources and also synthetic inhibitors are available. The best studied inhibitor is trichostatin A, a hydroxamic acid that exerts its activity by complexation of a zinc ion that is supposed to mediate the acetamide cleavage at the catalytic site. There are several synthetic hydroxamic acids that bear resemblance to trichostatin. Another class of potent inhibitors are naturally occurring and synthetic cyclotetrapeptides that all contain an unusual amino acid with an epoxyketone, ketone or hydroxamic acid function in the side chain. Phenylacetate, phenylbutyrate, butyrate and similar short chain fatty acids are also weak inhibitors. Further inhibitors from natural sources are the epoxide depudecin and depsipeptide FR 901228. The benzamide MS-275 belongs to a new class of synthetic HDAC inhibitors and displays oral activity in animal models. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer is possible. Thus, inhibitors of HDAC are one of the most promising class of new anticancer agents. New screening assays are useful tools that will facilitate identification of further inhibitors.
Insights
Histone deacetylase (HDAC) inhibitors are promising anticancer agents that induce cancer cell differentiation or apoptosis. Clinical studies show safe histone hyperacetylation in humans, advancing cancer treatment possibilities.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Histone deacetylase (HDAC) inhibitors represent an emerging class of anticancer agents.
- Aberrant histone acetylation, driven by HDAC activity, contributes to cancer pathogenesis.
- HDAC inhibitors induce chromatin hyperacetylation, leading to gene activation, cell differentiation, and apoptosis.
Purpose of the Study:
- To review the landscape of histone deacetylase (HDAC) inhibitors as anticancer agents.
- To highlight the mechanisms of action and diverse chemical classes of HDAC inhibitors.
- To discuss the clinical relevance and future prospects of HDAC inhibitors in cancer therapy.
Main Methods:
- Review of natural and synthetic HDAC inhibitors, including trichostatin A, cyclotetrapeptides, short-chain fatty acids, depudecin, FR 901228, and MS-275.
- Discussion of the molecular mechanisms involving zinc ion complexation and catalytic site interactions.
- Summary of findings from preclinical and early clinical studies.
Main Results:
- HDAC inhibitors induce terminal cell differentiation and/or apoptosis in cancer cells.
- Various classes of HDAC inhibitors exist, including hydroxamic acids, cyclotetrapeptides, and benzamides.
- Clinical studies demonstrate the safety of achieving histone hyperacetylation in humans.
Conclusions:
- HDAC inhibitors are a highly promising class of novel anticancer agents.
- Further development and identification of HDAC inhibitors are facilitated by new screening assays.
- HDAC inhibition offers a viable strategy for cancer treatment.