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Journal ArticleDOI

Histone deacetylase inhibitors.

Claude Monneret1
01 Jan 2005-European Journal of Medicinal Chemistry (Elsevier Masson)-Vol. 40, Iss: 1, pp 1-13
TL;DR: Design of a second generation ofHDACs was based upon data affording potent HDACs such as LAQ824 and PDX101 currently under phase I clinical trials, and two of them, MS-275 and CI-994, have reached phase II and I clinical Trials, respectively.
About: This article is published in European Journal of Medicinal Chemistry.The article was published on 2005-01-01. It has received 819 citations till now. The article focuses on the topics: Histone deacetylase & Phenylbutyrate.
Citations
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Journal ArticleDOI
TL;DR: Investigating aspects of HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols and help to understand the role of histone deacetylases in tumorigenesis.
Abstract: Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.

2,110 citations

Journal ArticleDOI
13 Aug 2007-Oncogene
TL;DR: This review focuses on the mechanisms of action of histone deacetylase ( HDAC) inhibitors (HDACi), a group of recently discovered ‘targeted’ anticancer agents that induces different phenotypes in various transformed cells.
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.

1,424 citations


Cites background from "Histone deacetylase inhibitors."

  • ...HDACi have been discovered with different structural characteristics, including hydroximates, cyclic peptides, aliphatic acids and benzamides (Table 2) (Miller et al., 2003; Yoshida et al., 2003; Marks and Breslow, 2007)....

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Journal ArticleDOI
TL;DR: This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota–gut–brain interactions and their interaction with gut–brain signalling pathways including immune, endocrine, neural and humoral routes.
Abstract: Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract, are speculated to have a key role in microbiota-gut-brain crosstalk. However, the pathways through which SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, research directly exploring the role of SCFAs as potential mediators of the effects of microbiota-targeted interventions on affective and cognitive functioning is sparse, especially in humans. This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota-gut-brain interactions. The effects of SCFAs on cellular systems and their interaction with gut-brain signalling pathways including immune, endocrine, neural and humoral routes are described. The effects of microbiota-targeted interventions such as prebiotics, probiotics and diet on psychological functioning and the putative mediating role of SCFA signalling will also be discussed, as well as the relationship between SCFAs and psychobiological processes. Finally, future directions to facilitate direct investigation of the effect of SCFAs on psychological functioning are outlined.

1,206 citations

Journal ArticleDOI
TL;DR: With the advent of numerous drugs that target specific enzymes involved in the epigenetic regulation of gene expression, the utilization of epigenetic targets is emerging as an effective and valuable approach to chemotherapy as well as chemoprevention of cancer.
Abstract: The initiation and progression of cancer is controlled by both genetic and epigenetic events. Unlike genetic alterations, which are almost impossible to reverse, epigenetic aberrations are potentially reversible, allowing the malignant cell population to revert to a more normal state. With the advent of numerous drugs that target specific enzymes involved in the epigenetic regulation of gene expression, the utilization of epigenetic targets is emerging as an effective and valuable approach to chemotherapy as well as chemoprevention of cancer.

1,155 citations

Journal ArticleDOI
23 Feb 2007-Cell
TL;DR: The functional relevance of spatial and temporal genome organization at three hierarchical levels: the organization of nuclear processes, the higher-order organization of the chromatin fiber, and the spatial arrangement of genomes within the cell nucleus are discussed.

1,140 citations

References
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Journal ArticleDOI
18 Sep 1997-Nature
TL;DR: The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it.
Abstract: The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it. Both histone/histone and histone/DNA interactions depend on the histone fold domains and additional, well ordered structure elements extending from this motif. Histone amino-terminal tails pass over and between the gyres of the DNA superhelix to contact neighbouring particles. The lack of uniformity between multiple histone/DNA-binding sites causes the DNA to deviate from ideal superhelix geometry.

7,841 citations

Journal ArticleDOI
19 Oct 2001-Cell
TL;DR: It is proposed that hSir2, the human homolog of the S. cerevisiae Sir2 protein known to be involved in cell aging and in the response to DNA damage, binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue.

2,500 citations

Journal ArticleDOI
19 Oct 2001-Cell
TL;DR: It is shown that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions, and Nicotinamide inhibits an NAD-dependent p53 deacetylation induced by Sir2 alpha, and also enhances the p53 acetylation levels in vivo.

2,021 citations

Journal ArticleDOI
TL;DR: Results clearly indicate that TSA is a potent and specific inhibitor of the histone deacetylase and that the in vivo effect of TSA on cell proliferation and differentiation can be attributed to the inhibition of the enzyme.

1,897 citations

Journal ArticleDOI
TL;DR: Valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients, and tumor growth and metastasis formation are significantly reduced in animal experiments, suggesting that it might serve as an effective drug for cancer therapy.
Abstract: Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.

1,785 citations