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《Expert opinion on investigational drugs》2013,22(12):2923-2934
Compounds that inhibit histone deacetylase may enable the re-expression of silenced regulatory genes in neoplastic cells, reversing the malignant phenotype. Although several molecules that inhibit histone deacetylase are undergoing preclinical development, butyric acid derivatives have undergone clinical investigation for several years, initially for non-malignant indications and more recently for the treatment of cancer. Of the butyric acid derivatives, sodium phenylbutyrate has undergone the most extensive systematic investigation. Administration of phenylbutyrate by iv. and oral routes is well-tolerated clinically at concentrations which effect acetylation of histones in vitro. Higher doses lead to reversible CNS depression. The studies presented to date have been Phase I studies and do not enable assessment of efficacy. However, current development of phenylbutyrate is proceeding in combination with other agents based on rational biologically-based in vitro studies. The parallel development of combination therapy including phenylbutyrate and early clinical development of other, more potent histone deacetylase inhibitors will hopefully lead to feasible, clinically tolerable strategies for altering the malignant phenotype of cancer cells. 相似文献
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Peggy Papeleu Tamara Vanhaecke Greetje Elaut Mathieu Vinken Tom Henkens Sarah Snykers 《Critical reviews in toxicology》2013,43(4):363-378
Histone deacetylase (HDAC) inhibitors target key steps of tumor development: They inhibit proliferation, induce differentiation and/or apoptosis, and exhibit potent antimetastatic and antiangiogenic properties in transformed cells in vitro and in vivo. Preliminary studies in animal models have revealed a relatively high tumor selectivity of HDAC inhibitors, strenghtening their promising potential in cancer chemotherapy. Until now, preclinical in vitro research has almost exclusively been performed in cancer cell lines and oncogene-transformed cells. However, as cell proliferation and apoptosis are essential for normal tissue and organ homeostasis, it is important to investigate how HDAC inhibitors influence the regulation of and interplay between proliferation, differentiation, and apoptosis in primary cells as well. This review highlights the discrepancies in molecular events triggered by trichostatin A, the reference compound of hydroxamic acid-containing HDAC inhibitors, in hepatoma cells and primary hepatocytes (which are key targets for drug-induced toxicity). The implications of these differential outcomes in both cell types are discussed with respect to both toxicology and drug development. In view of the future use of HDAC inhibitors as cytostatic drugs, it is highly recommended to include both tumor cells and their healthy counterparts in preclinical developmental studies. Screening the toxicological properties of compounds early in their development process, using a battery of different cell types, will enable researchers to discard those compounds bearing undesirable adverse activity before entering into expensive clinical trials. This will not only reduce the risk for harmful exposure of patients but also save time and money. 相似文献
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A balance between rapid, short lived, neuronal responses and prolonged ones fulfill the biochemical and cellular requirements for creating a molecular memory. I provide an overview of epigenetic mechanisms in the brain and discuss their impact on synaptic plasticity, cognitive functions, and discuss a recent example of how they can contribute to neurodegeneration and the cognitive decline associated with Alzheimer's disease. 相似文献
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Studies on the chitin/chitosan binding properties of six cuticular proteins analogous to peritrophin 3 from Bombyx mori 下载免费PDF全文
Chitin deacetylation is required to make the cuticle rigid and compact through chitin chain crosslinking. Thus it is presumed that specialized proteins are required to bind deacetylated chitin chains together. However, deacetylated‐chitin binding proteins have not ever been reported. In a previous work, six cuticular proteins analogous to peritrophin 3 (CPAP3s) were found to be abundant in the moulting fluid of Bombyx mori. In this study, these BmCPAP3s (BmCPAP3‐A1, BmCPAP3‐A2, BmCPAP3‐B, BmCPAP3‐C, BmCPAP3‐D1 and BmCPAP3‐D2) were cloned and expressed in Escherichia coli and purified using metal‐chelating affinity chromatography. Their binding activities demonstrated that although all of the BmCPAP3s showed similar binding abilities toward crystalline chitin and colloidal chitin, they differed in their affinities toward partially and fully deacetylated chitin. Amongst them, BmCPAP3‐D1 exhibited the highest binding activity toward deacetylated chitin. The gene expression pattern of BmCPAP3‐D1 was similar to BmCPAP3‐A1 and BmCPAP3‐C at most stages except that it was dramatically upregulated at the beginning of the pupa to adult transition stage. This work is the first report of a chitin‐binding protein, BmCPAP3‐D1, which exhibits high binding affinity to deacetylated chitin. 相似文献
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Histone deacetylase (HDAC) inhibitors, which represent a structurally diverse group of molecules, have emerged as a novel therapeutic class of molecules with significant anticancer potential. Vorinostat and romidepsin, known as the first generation of HDAC inhibitors, were approved in the United States for the treatment of T-cell lymphomas. Preliminary activity of HDAC inhibitors has also been observed in non-small cell lung cancer (NSCLC) in combination with the existing treatment regimens, of which is the focus of the current review. 相似文献
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Neuroblastoma is predominantly characterised by chromosomal rearrangements. Next to V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog (MYCN) amplification, chromosome 7 and 17q gains are frequently observed. We identified a neuroblastoma patient with a regional 7q36 gain, encompassing the enhancer of zeste homologue 2 (EZH2) gene. EZH2 is the histone methyltransferase of lysine 27 of histone H3 (H3K27me3) that forms the catalytic subunit of the polycomb repressive complex 2. H3K27me3 is commonly associated with the silencing of genes involved in cellular processes such as cell cycle regulation, cellular differentiation and cancer. High EZH2 expression correlated with poor prognosis and overall survival independent of MYCN amplification status. Unexpectedly, treatment of 3 EZH2-high expressing neuroblastoma cell lines (IMR32, CHP134 and NMB), with EZH2-specific inhibitors (GSK126 and EPZ6438) resulted in only a slight G1 arrest, despite maximum histone methyltransferase activity inhibition. Furthermore, colony formation in cell lines treated with the inhibitors was reduced only at concentrations much higher than necessary for complete inhibition of EZH2 histone methyltransferase activity. Knockdown of the complete protein with three independent shRNAs resulted in a strong apoptotic response and decreased cyclin D1 levels. This apoptotic response could be rescued by overexpressing EZH2ΔSET, a truncated form of wild-type EZH2 lacking the SET transactivation domain necessary for histone methyltransferase activity. Our findings suggest that high EZH2 expression, at least in neuroblastoma, has a survival function independent of its methyltransferase activity. This important finding highlights the need for studies on EZH2 beyond its methyltransferase function and the requirement for compounds that will target EZH2 as a complete protein. 相似文献
58.
Histone acetyltransferases and histone deacetylases (HDACs) are multifunctional enzymes that posttranslationally modify both histone and nonhistone acetylation sites, affecting a broad range of cellular processes (e.g., cell cycle, apoptosis, and protein folding) often dysregulated in cancer. HDAC inhibitors are small molecules that directly interact with HDAC catalytic sites preventing the removal of acetyl groups, thereby counteracting the effects of HDACs. Since the first HDAC inhibitor, valproic acid, was investigated as a potential antitumor agent, there have been a number of other HDAC inhibitors developed to improve efficacy and safety. Despite significant progress in the management of patients with hematologic malignancies, overall survival is still poor. The discovery that HDACs may play a role in hematologic malignancies and preclinical studies showing promising activity with HDAC inhibitors in various tumor types, led to clinical evaluation of HDAC inhibitors as potential treatment options for patients with advanced hematologic malignancies. The Food and Drug Administration has approved two HDAC inhibitors, vorinostat (2006) and romidepsin (2009), for the treatment of cutaneous T-cell lymphoma. This review highlights the safety of HDAC inhibitors currently approved or being investigated for the treatment of hematologic malignancies, with a specific focus on the safety experience with vorinostat in cutaneous T-cell lymphoma. 相似文献
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