Gene/Protein Disease Symptom Drug Enzyme Compound
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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone deacetylases (HDACs) are an emerging class of novel anti-cancer drug targets. Recently, studies in adult cancers and in neuroblastoma have shown that individual HDAC family members are aberrantly expressed in tumors and correlate with disease stage and prognosis. In neuroblastoma, knockdown of individual HDAC family members causes distinct phenotypes ranging from differentiation to apoptosis. HDACs are involved in controlling MYCN function and are upregulated in chemotherapy-resistant neuroblastoma cells. Treatment with unselective pan-HDAC inhibitors causes cell cycle arrest, differentiation, apoptosis, and inhibition of clonogenic growth of neuroblastoma cells, and restores susceptibility to chemotherapy treatment. The molecular mechanisms mediating the anti-cancer effects of HDAC inhibitors on neuroblastoma cells are incompletely understood and involve targeting of aberrant epigenetic repression of tumor suppressor genes, activation of developmental differentiation pathways, as well as changing the acetylation level and function of non-histone proteins. In neuroblastoma mouse models, unselective HDAC inhibitors demonstrate anti-tumoral effects. First phase I clinical trials in children with refractory cancers using HDAC inhibitors depsipeptide and the recently approved vorinostat are underway. This review summarizes our current knowledge about classical HDAC family members as novel drug targets for neuroblastoma therapy and discusses the potential role of next generation, selective HDAC inhibitors.
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PMID:Targeting histone deacetylases in neuroblastoma. 1919 71

Histone deacetylases (HDACs) are a family of enzymes found in bacteria, fungi, plants, and animals that profoundly affect cellular function by catalyzing the removal of acetyl groups from -N-acetylated lysine residues of various protein substrates including histones, transcription factors, alpha-tubulin, and nuclear importers. Although the precise roles of HDAC isoforms in cellular function are not yet completely understood, inhibition of HDAC activity has emerged as a promising approach for reversing the aberrant epigenetic states associated with cancer and other chronic diseases. Potent new isoform-selective HDAC inhibitors would therefore help expand our understanding of the HDAC enzymes and represent attractive lead compounds for drug design, especially if combined with high-resolution structural analyses of such inhibitors to shed light on the three-dimensional pharmacophoric features necessary for the future design of more potent and selective compounds. Here we present structural and functional analyses of a series of beta-amino-acid-containing HDAC inhibitors inspired by cyclic tetrapeptide natural products. To survey a diverse ensemble of pharmacophoric configurations, we systematically varied the position of the beta-amino acid, amino acid chirality, functionalization of the Zn(2+)-coordinating amino acid side chain, and alkylation of the backbone amide nitrogen atoms around the macrocycle. In many cases, the compounds were a single conformation in solution and exhibited potent activities against a number of HDAC isoforms as well as effective antiproliferative and cytotoxic activities against human tumor cells. High-resolution NMR solution structures were determined for a selection of the inhibitors, providing a useful means of correlating detailed structural information with potency. The structure-based approach described here is expected to furnish valuable insights toward the future design of more selective HDAC inhibitors.
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PMID:Design, synthesis, biological evaluation, and structural characterization of potent histone deacetylase inhibitors based on cyclic alpha/beta-tetrapeptide architectures. 1923 70

Histone Deacetylase (HDAC) inhibitors represent a budding class of targeted anti-cancer agents. This structurally diverse group of molecules can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. Of the different classes of HDAC the class I and Class II are considered the main targets for cancer. For the two classes of HDAC, only a few compounds have emerged as preferential inhibitors and even fewer are able to discriminate efficiently among HDACs in the same class. This limitation has diminutive relevance to the use of HDAC inhibitors as potential anti-tumor drugs. Hence, the four HDACs of class I was modeled and about twelve known inhibitors which are currently under the phase I/II trials were docked using an efficient shape-based search algorithm and the AScore scoring function, to each of the class I HDAC members in order to identify the inhibitor or group with better pharmacological action. The molecular descriptors study and the drug score, drug likeness prediction helped in the identification of potential compounds targeting specific enzymes of HDAC family. The ranking of various groups of ligands helped in the identification of potential groups and better compound that can better target class I HDAC in an effective way.
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PMID:Assessment for the identification of better HDAC inhibitor class through binding energy calculations and descriptor analysis. 1925 37

Tumorigenesis is traditionally thought to be caused by the imbalance between oncogenes and tumor-suppressor genes. Epigenetics is a recently described phenomenon that uses an alternative mechanism to explain the transcriptional inactivation of tumor-suppressor genes predominantly by hypermethylation of the promoter regions. Hypermethylation of these regions has been described extensively in many neoplasms, including cutaneous melanoma. Histone modification, primarily by acetylation and deacetylation, is a current potential target for melanoma therapy, but more research is required to understand the mechanisms involved and the therapeutic effectiveness of regimens involving these agents. These mechanisms not only are important for understanding the origin and progression of neoplasms but also have important potential therapeutic implications. Understanding the epigenetic mechanisms involved in melanoma can provide valuable information with significant implications in diagnosis, treatment, and prevention.
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PMID:Epigenetics of cutaneous melanoma. 1925 5

Human histone gene expression is controlled at the level of transcription initiation and subsequent 3'end processing to generate non-polyadenylated stem-loop containing histone mRNAs. Transcription is controlled at the G1/S phase transition by the Cyclin E/CDK2 mediated induction of p220(NPAT)/HiNF-P complexes at subnuclear domains designated Histone Locus Bodies (HLBs) that associate with histone gene clusters. Histone mRNA maturation is mediated by Lsm10 containing U7snRNP complexes. In normal human somatic and embryonic stem cells, the 6p histone locus, the transcription marker p220(NPAT) and the 3'end processing marker Lsm10 (but not the Cajal Body marker coilin) co-localize, reflecting the assembly of an integrated factory for histone gene expression. Using in situ immuno-fluorescence microscopy and fluorescence in situ hybridization (FISH), we show that this subnuclear organization is compromised in some cancer cell lines. In aneuploid cells, the presence of HLBs correlates with the number of histone gene loci. More importantly, the in situ co-localization of p220(NPAT) and Lsm10 is disrupted in HeLa S3 cervical carcinoma cells and MCF7 breast adenocarcinoma cells, with most Lsm10 residing in Cajal Bodies. The finding that the subnuclear integration of transcriptional initiation and 3'end processing of histone gene transcripts is deregulated may be causally linked to tumor-related modifications in molecular pathways controlling histone gene expression during the cell cycle.
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PMID:The subnuclear organization of histone gene regulatory proteins and 3' end processing factors of normal somatic and embryonic stem cells is compromised in selected human cancer cell types. 1927 82

Histone deacetylases (HDACs) have emerged as attractive drug targets, particularly for neoplastic indications. This large family is divided into four classes, of which three consist of zinc-dependent enzymes, and inhibitors of these are the subject of this review. Currently, there are several inhibitors advancing through clinical trials, all of which inhibit multiple isoforms of these three classes. While promising, these compounds have exhibited toxicities in the clinic that might limit their potential, particularly in solid tumors. It may be possible to reduce some of the toxicity by specifically targeting only the isoform(s) involved in maintaining that particular tumor and spare other isoforms that are uninvolved or even beneficial. This review examines the selectivity and toxicity of HDAC inhibitors currently in clinic, comparing pan-HDAC inhibitors to Class I selective compounds. The rationale for isoform-specific inhibitors is examined. The current status of isoform-specific inhibitor development is analyzed, especially inhibitors of HDAC1, 2, 4 and 8 enzymes, and the potential clinical utility of these compounds is discussed.
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PMID:Isoform-specific histone deacetylase inhibitors: the next step? 1928 55

Absent or altered differentiation is one of the major features of cancer cells. Histone deacetylases (HDACs) play a central role in the epigenetic regulation of gene expression. Aberrant activity of HDACs has been documented in several types of cancers, leading to the development of HDAC inhibitors (HDACi) as anti-tumor drugs. In vitro and in vivo experimental evidences show that HDACi are able to resume the process of maturation in undifferentiated cancer cells, justifying their introduction as differentiating agents in several clinical trials. Modulation of cell fate by HDACi is observed at several levels, including the stem cell compartment: HDACi can act both on cancer stem cells, and with the rest of the tumor cell mass, leading to complex biological outputs. As a note of caution, when used as single agent, HDACi show only a moderate and limited biological response, which is augmented in combinatorial therapies with drugs designed against other epigenetic targets. The optimal employment of these molecules may be therefore in combination with other epigenetic drugs acting against the set of enzymes responsible for the set-up and maintenance of epigenetic information.
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PMID:Histone deacetylase inhibitors as a new weapon in the arsenal of differentiation therapies of cancer. 1934

The balance of histone acetylation and deacetylation is an epigenetic layer with a critical role in the regulation of gene expression. Histone acetylation induced by histone acetyl transferases (HATs) is associated with gene transcription, while histone hypoacetylation induced by histone deacetylase (HDAC) activity is associated with gene silencing. Altered expression and mutations of genes that encode HDACs have been linked to tumor development since they both induce the aberrant transcription of key genes regulating important cellular functions such as cell proliferation, cell-cycle regulation and apoptosis. Thus, HDACs are among the most promising therapeutic targets for cancer treatment, and they have inspired researchers to study and develop HDAC inhibitors.
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PMID:The role of histone deacetylases (HDACs) in human cancer. 1938 84

Combined targeting of distinct cellular signaling mechanisms may improve the efficacy and reduce the toxicity of therapy in pancreatic cancer. Histone deacetylases (HDACs) control cellular functions through epigenetic modulation, and HDACs inhibitors suppress cell growth in pancreatic adenocarcinoma. The Hedgehog (Hh) pathway regulates the development of the pancreas, and aberrant Hh signaling promotes the initiation and progression of pancreatic neoplasia. We hypothesize that HDACs and the Hh pathway cooperatively interact to regulate cellular proliferation of the exocrine pancreas. A combination of the HDAC inhibitor SAHA and the Smoothened antagonist SANT-1 was evaluated for their ability to suppress growth of the Gemcitabine-resistant pancreatic adenocarcinoma cell lines Panc-1 and BxPC-3. The combination of SAHA and SANT-1 supra-additively suppressed cellular proliferation and colony formation. Flow cytometric and immunohistochemical analyses indicated that enhanced induction of apoptotic cell death, cell cycle arrest in G(0)/G(1) phase, and ductal epithelial differentiation are involved. Cell death was associated with nuclear localization of survivin, increased bax expression, and activation of caspases 3 and 7. Consistent with the cell cycle arrest and cytodifferentiation, the cyclin-dependent kinase inhibitors p21(waf) and p27(kip1) were upregulated, and cyclin D1 downregulated. The potentiated anti-proliferative effect by the combination of SAHA and SANT-1 may involve cooperative suppression of the Hh pathway activity, as shown by the upregulation of HHIP by SAHA, and enhanced repression of of Ptc-1 mRNA expression. In summary, we have developed a molecular target-based therapeutic approach that overcomes chemoresistance in pancreatic cancer cells by chemically inhibiting HDACs and Hh signaling in combination.
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PMID:Combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer. 1944 37

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma and B-lymphocyte disorders, primary effusion lymphoma (PEL) and Multicentric Castleman's Disease (MCD). KSHV usually exists in a latent form in which the viral genome is circularized into an extrachormosomal episome. However, induction of lytic replication by environmental stimuli or chemical agents is important for the spread of KSHV. The switch between latency and lytic replication is regulated by epigenetic factors. Hypomethylation of the promoter of replication and transcription activator (RTA), which is essential for the lytic switch, leads to KSHV reactivation. Histone acetylation induces KSHV replication by influencing protein-protein-associations and transcription factor binding. Histone modifications also determine chromatin structure and nucleosome positioning, which are important for KSHV DNA replication during latency. The association of KSHV proteins with chromatin remodeling complexes promotes the open chromatin structure needed for transcription factor binding and DNA replication. Additionally, post-translational modification of KSHV proteins is important for the regulation of RTA activity and KSHV replication. KSHV may also cause epigenetic modification of the host genome, contributing to promoter hypermethylation of tumor suppressor genes in KSHV-associated neoplasias.
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PMID:Epigenetic regulation of Kaposi's sarcoma-associated herpesvirus replication. 1942 78


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