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Histone deacetylase inhibitors: molecular mechanisms of action

Abstract

This review focuses on the mechanisms of action of histone deacetylase (HDAC) inhibitors (HDACi), a group of recently discovered ‘targeted’ anticancer agents. There are 18 HDACs, which are generally divided into four classes, based on sequence homology to yeast counterparts. Classical HDACi such as the hydroxamic acid-based vorinostat (also known as SAHA and Zolinza) inhibits classes I, II and IV, but not the NAD+-dependent class III enzymes. In clinical trials, vorinostat has activity against hematologic and solid cancers at doses well tolerated by patients. In addition to histones, HDACs have many other protein substrates involved in regulation of gene expression, cell proliferation and cell death. Inhibition of HDACs causes accumulation of acetylated forms of these proteins, altering their function. Thus, HDACs are more properly called ‘lysine deacetylases.’ HDACi induces different phenotypes in various transformed cells, including growth arrest, activation of the extrinsic and/or intrinsic apoptotic pathways, autophagic cell death, reactive oxygen species (ROS)-induced cell death, mitotic cell death and senescence. In comparison, normal cells are relatively more resistant to HDACi-induced cell death. The plurality of mechanisms of HDACi-induced cell death reflects both the multiple substrates of HDACs and the heterogeneous patterns of molecular alterations present in different cancer cells.

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Acknowledgements

The studies reported in this paper from the authors' laboratory have been supported, in part, by grants from the National Institute of Health (P30CA08748-41), Jack and Susan Rudin Foundation, David H Koch Foundation, and the Prostate Cancer Research Award, Experimental Therapeutics Center at Memorial Sloan-Kettering Cancer Center and the DeWitt Wallace Research Fund. MSKCC and Columbia University jointly hold patents on hydroxamic acid-based polar compounds, including vorinostat (SAHA), that were exclusively licensed to Aton Pharma Inc., a biotechnology company that was acquired by Merck Inc. in April 2004. PAM was a founder of Aton and has a financial interest in Merck's further development of vorinostat.

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Xu, W., Parmigiani, R. & Marks, P. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26, 5541–5552 (2007). https://doi.org/10.1038/sj.onc.1210620

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