Prospects: Histone deacetylase inhibitors Journal Article
| Authors: | Dokmanovic, M.; Marks, P. A. |
| Article Title: | Prospects: Histone deacetylase inhibitors |
| Abstract: | Histone deacetylase (HDAC), inhibitors represent a new class of targeted anti-cancer agents. Several of these compounds are in clinical trials with significant activity against a spectrum of both hematologic and solid tumors at doses that are well tolerated by the patients. The HDAC inhibitors are a structurally diverse group of molecules that can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. While the base sequence of DNA provides the genetic code for proteins, the expression of genes is regulated, in large part, by the structure of the chromatin proteins around which the DNA is wrapped (epigenetic gene regulation). The acetylation and deacetylation of the lysines in the tails of the core histones, among the most extensively studied aspects of chromatin structure, is controlled by the action of two families of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs). Protein components of transcription factor complexes and many other non-histone proteins are also substrates for HDACs and HATs. The structure and activity of these non-histone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. This review focuses on several key questions with respect to the mechanism of action of HDACi, including, what are the different cell phenotypes induced by HDACi, why are normal cells compared to transformed cells relatively resistant to HDACi induced cell death, why are certain tumors more responsive to HDACi than others, and what is the basis of the selectivity of HDACi in altering gene expression. The answers to these questions will have therapeutic importance since we will identify targets for enhancing the efficacy and safety of HDACi. © 2005 Wiley-Liss, Inc. |
| Keywords: | cancer chemotherapy; unclassified drug; human cell; fludarabine; histone deacetylase inhibitor; clinical trial; angiogenesis inhibitor; drug efficacy; drug potentiation; drug safety; nonhuman; solid tumor; drug targeting; antineoplastic agent; dna synthesis; cell proliferation; mouse; animals; cell cycle; imatinib; unindexed drug; apoptosis; bortezomib; proteasome inhibitor; enzyme inhibition; phase 2 clinical trial; gene expression; animal experiment; animal model; t cell lymphoma; drug mechanism; enzyme inhibitors; cell transformation; vorinostat; crystal structure; tumor model; flavopiridol; phase 1 clinical trial; drug cytotoxicity; natural product; enzyme structure; histone deacetylases; oxidation reduction reaction; oxidation-reduction; cyclopeptide; valproic acid; histone deacetylase; deacetylation; 3 phenylsulfamoylcinnamohydroxamic acid; arylbutyric acid derivative; n (2 aminophenyl) 4 (3 pyridinylmethoxycarbonylaminomethyl)benzamide; 4 [n (2 hydroxyethyl) n [2 (3 indolyl)ethyl]aminomethyl]cinnamohydroxamic acid; 4 n acetyldinaline; sk 7041; trichostatin a; acetylation; chromatin structure; depsipeptide; gene expression regulation, enzymologic; hematopoietic system tumor; benzamide derivative; hydroxamic acid derivative; thioredoxin; myeloma cell; fr 901228; oxamflatin; thioredoxin-binding protein; transcription factor complex; aliphatic carboxylic acid; lbh 589a; sk 7046 |
| Journal Title: | Journal of Cellular Biochemistry |
| Volume: | 96 |
| Issue: | 2 |
| ISSN: | 0730-2312 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2005-10-01 |
| Start Page: | 293 |
| End Page: | 304 |
| Language: | English |
| DOI: | 10.1002/jcb.20532 |
| PUBMED: | 16088937 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 245" - "Export Date: 24 October 2012" - "CODEN: JCEBD" - "Source: Scopus" |
