Histone Deacetylase Inhibitors

A dynamic equilibrium of histone acetyltransferase and histone deacetylase (HDAC) controls the level of acetylated histones in nuclear chromatin. By inducing acetylation of the nuclear histones H3 and H4, HDAC inhibitors (HDACI) alter chromatin structure, affecting transcription of several genes, and resulting in growth arrest, differentiation, and apoptosis of tumor cells (Kuo and Allis 1998). Deregulation of his-tone acetylation has been implicated in the development of several types of cancer. Genes that encode HAT enzymes are translocated, amplified, over-expressed, and/or mutated in various cancers. Two closely related HATs, CBP and p300, are altered in some tumors by either mutation or translocation. A number of new compounds have been developed which inhibit HDAC activity. The best-known examples of this class of agents are the butyrates; however, the butyrates have a short plasma half-life and it is difficult to achieve therapeutic concentrations of bu-tyrates in the plasma. Other compounds that have been developed more recently include depsipeptide (FK-228; Furumai et al. 2002), CBHA, suberoylanilide hydroxamic acid (SAHA), oxamflatin, depudecin, and MS-275 (Yoshida et al. 2001; Marks et al. 2004).

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