Histone deacetylase inhibitors: Molecular mechanisms of action Journal Article
| Authors: | Xu, W. S.; Parmigiani, R. B.; Marks, P. A. |
| Article Title: | 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. © 2007 Nature Publishing Group All rights reserved. |
| Keywords: | signal transduction; unclassified drug; mutation; histone deacetylase inhibitor; itf 2357; drug tolerability; review; cisplatin; doxorubicin; solid tumor; antineoplastic agents; gemcitabine; antineoplastic agent; protein function; neoplasms; cell proliferation; mitosis; phenotype; cell death; imatinib; unindexed drug; apoptosis; bortezomib; enzyme inhibition; gene expression; protein protein interaction; etoposide; protein binding; drug resistance, neoplasm; enzyme substrate; drug selectivity; angiogenesis; cell heterogeneity; docetaxel; molecular mechanics; gene activation; cutaneous t cell lymphoma; enzyme inhibitors; cell transformation; substrate specificity; vorinostat; reactive oxygen metabolite; cell cycle arrest; epirubicin; gene control; 5 aza 2' deoxycytidine; senescence; yeast; sequence homology; autophagy; trastuzumab; cyclin dependent kinase inhibitor; floxuridine; histone deacetylases; phosphotransferase inhibitor; retinoid; histone deacetylase; deacetylation; 2 morpholino 8 phenylchromone; 3 phenylsulfamoylcinnamohydroxamic acid; n (2 aminophenyl) 4 (3 pyridinylmethoxycarbonylaminomethyl)benzamide; nicotinamide adenine dinucleotide; pivaloyloxymethyl butyrate; growth disorder; epothilone b; geldanamycin; pci 24781; ellipticine; midostaurin; colecalciferol; fr 901228; lbh 589; mgcd 0103; mitotic cell death; 17 ally amino demethoxy geldanamycin; baceca; flavopyridol; phosphatidylinocitol 3 kinase inhibitor; savicol |
| Journal Title: | Oncogene |
| Volume: | 26 |
| Issue: | 37 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2007-08-13 |
| Start Page: | 5541 |
| End Page: | 5552 |
| Language: | English |
| DOI: | 10.1038/sj.onc.1210620 |
| PUBMED: | 17694093 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 368" - "Export Date: 17 November 2011" - "CODEN: ONCNE" - "Source: Scopus" |
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