Inhibition of histone deacetylases: a new strategy to target epigenetic modifications for anticancer treatment.
The role of epigenetic modifications due to deregulated acetylation of nucleosomes with respect to its role in progression and etiology of human cancer is discussed. Among the mediators of these phenomena are the histone deacetylases, a class of enzymes consisting of at least two subfamilies with a total of at least 7 members in mammals. Depending on the cell-type, inhibition of HDACs in cancer cells can lead to transcriptional activation and silencing of about 2% of human genes, cell-cycle arrest and induction of apoptosis and differentiation in vitro and in vivo. This paper discusses several inhibitors of HDACs primarily derived from natural sources, their physiological consequences in different in vitro and in vivo cancer-related systems, their stage of preclinical and clinical development as well as their potential as antineoplastic agents. It is of paramount importance to elucidate the molecular mechanisms resulting in cell-cycle arrest, apoptosis or differentiation after inhibition of HDACs and to investigate the physiological function of the different HDAC isoenzymes and their deregulation in human cancers in order to devise optimized therapeutic intervention in cancer patients.
Roche Diagnostics GmbH, Penzberg, Germany. Ulrich.Weidle@roche.com
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Weidle
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Grossmann
D000107:Acetylation; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D047630:Depsipeptides; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D010455:Peptides; D010456:Peptides, Cyclic
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010455:Peptides; D010456:Peptides, Cyclic; C067070:trapoxin A; C087123:romidepsin; D006655:Histone Deacetylases