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Search Results: 1 - 10 of 2263 matches for " histone deacetylase inhibition "
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Epigenetic modulation in the treatment of atherosclerotic disease
Mikaela M. Byrne,Anthony W. Ryan
Frontiers in Genetics , 2014, DOI: 10.3389/fgene.2014.00364
Abstract: Cardiovascular disease is the single largest cause of death in the western world and its incidence is on the rise globally. Atherosclerosis, characterized by the development of atheromatus plaque, can trigger luminal narrowing and upon rupture result in myocardial infarction or ischemic stroke. Epigenetic phenomena are a focus of considerable research interest due to the role they play in gene regulation. Epigenetic mechanisms such as DNA methylation and histone acetylation have been identified as potential drug targets in the treatment of cardiovascular disease. miRNAs are known to play a role in gene silencing, which has been widely investigated in cancer. In comparison, the role they play in cardiovascular disease and plaque rupture is not well understood. Nutritional epigenetic modifiers from dietary components, for instance sulforaphane found in broccoli, have been shown to suppress the pro-inflammatory response through transcription factor activation. This review will discuss current and potential epigenetic therapeutics for the treatment of cardiovascular disease, focusing on the use of miRNAs and dietary supplements such as sulforaphane and protocatechuic aldehyde.
Combination of suberoylanilide hydroxamic acid with heavy ion therapy shows promising effects in infantile sarcoma cell lines
Susanne Oertel, Markus Thiemann, Karsten Richter, Klaus-J Weber, Peter E Huber, Ramon Perez, Stephan Brons, Marc Bischof, Andreas E Kulozik, Volker Ehemann, Jürgen Debus, Claudia Blattmann
Radiation Oncology , 2011, DOI: 10.1186/1748-717x-6-119
Abstract: Clonogenic assays after different doses of heavy ions were performed. DNA damage and repair were evaluated by measuring γH2AX via flow-cytometry. Apoptosis and cell cycle analysis were also measured via flow cytometry. Protein expression of repair proteins, p53 and p21 were measured using immunoblot analysis. Changes of nuclear architecture after treatment with SAHA and HIT were observed in one of the sarcoma cell lines via light microscopy after staining towards chromatin and γH2AX.Corresponding with previously reported photon data, SAHA lead to an increase of sensitivity to heavy ions along with an increase of DSB and apoptosis in the two sarcoma cell lines. In contrast, in the osteoblast cell line (hFOB 1.19), the combination of SAHA and HIT showed a significant radio-protective effect. Laser scanning microscopy revealed no significant morphologic changes after HIT compared to the combined treatment with SAHA. Immunoblot analysis revealed no significant up or down regulation of p53. However, p21 was significantly increased by SAHA and combination treatment as compared to HIT only in the two sarcoma cell lines - again in contrast to the osteoblast cell line. Changes in the repair kinetics of DSB p53-independent apoptosis with p21 involvement may be part of the underlying mechanisms for radio-sensitization by SAHA.Our in vitro data suggest an increase of the therapeutic ratio by the combination of SAHA with HIT in infantile sarcoma cell lines.HDAC inhibitors (HDACI) induce growth arrest and affect cell differentiation, apoptosis and anti-angiogenic effects in tumor cells by chromatin modification with both transcription-dependent and independent mechanisms implicated [1,2].Suberoylanilide hydroxamic acid (SAHA) is the first HDACI that has been approved in the United States by the Food and Drug Administration (FDA) for the treatment of relapsed and refractory cutaneous T-cell lymphoma. It has also shown promising preclinical results in vitro and in vivo for several
In vivo efficacy of the histone deacetylase inhibitor suberoylanilide hydroxamic acid in combination with radiotherapy in a malignant rhabdoid tumor mouse model
Markus Thiemann, Susanne Oertel, Volker Ehemann, Wilko Weichert, Albrecht Stenzinger, Marc Bischof, Klaus-J Weber, Ramon Perez, Uwe Haberkorn, Andreas E Kulozik, Jürgen Debus, Peter E Huber, Claudia Battmann
Radiation Oncology , 2012, DOI: 10.1186/1748-717x-7-52
Abstract: Potential radiosensitization by SAHA was assessed in MRT xenografts by analysis of tumor growth delay, necrosis (HE), apoptosis (TUNEL), proliferation (ki-67) and γH2AX expression as well as dynamic 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG -PET) after treatment with either SAHA alone, single-dose (10 Gy) or fractionated XRT (3 × 3Gy) solely as well as in combination with SAHA compared to controls.SAHA only had no significant effect on tumor growth. Combination of SAHA for 8 days with single-dose XRT resulted in a higher number of complete remissions, but failed to prove a significant growth delay compared to XRT only. In contrast fractionated XRT plus SAHA for 3 weeks did induce significant tumor growth delay in MRT-xenografts.The histological examination showed a significant effect of XRT in tumor necrosis, expression of Ki-67, γH2AX and apoptosis. SAHA only had no significant effect in the histological examination. Comparison of xenografts treated with XRT and XRT plus SAHA revealed a significantly increased γH2AX expression and apoptosis induction in the mice tumors after combination treatment with single-dose as well as fractionated XRT. The combination of SAHA with XRT showed a tendency to increased necrosis and decrease of proliferation compared to XRT only, which, however, was not significant. The 18F-FDG-PET results showed no significant differences in the standard uptake value or glucose transport kinetics after either treatment.SAHA did not have a significant effect alone, but proved to enhance the effect of XRT in our MRT in vivo model.The aim of the present study was to evaluate the in vivo efficacy of the HDACi SAHA in combination with XRT in MRT xenotransplants.MRT and their central nervous system counterpart atypical teratoid/rhabdoid tumors are rare and highly malignant neoplasms that primarily occur in young children. Emerging evidence suggests an important role for radiotherapy to achieve long-term survival. Nevertheless even af
Novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction in oral squamous cell carcinoma  [PDF]
Osamu Takahashi, Toshinori Okinaga, Kenjiro Iwanaga, Manabu Habu, Wataru Ariyoshi, Kazuhiro Tominaga, Norikazu Nishino, Tatsuji Nishihara
Journal of Biophysical Chemistry (JBPC) , 2011, DOI: 10.4236/jbpc.2011.23026
Abstract: Epigenetic modifications such as histone deacetylation are commonly related to tumor development and histone deacetylase (HDAC) inhibitors have been shown to be potential drugs for cancer treatment. In the present study, we investigated the effects of a novel HDAC inhibitor, Ky-2, on oral squamous carcinoma cells in vitro. Cell viability was significantly reduced by treatment with Ky-2 at 25 nM, while it also led to augmentation of the proportion of cells in the sub-G1 phase and DNA fragmentation. In addition, immunoblot analysis revealed that Ky-2 enhanced the expression of apoptosis-related proteins. Our results showed that a low concentration of Ky-2 induced apoptosis in oral squamous carcinoma cells via activation of apoptotic cascades.
Epigenetic Therapy in Human Choriocarcinoma
Noriyuki Takai,Hisashi Narahara
Cancers , 2010, DOI: 10.3390/cancers2031683
Abstract: Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in choriocarcinomas, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. HDAC inhibitors (HDACIs) were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and the expression of genes related to the malignant phenotype in choriocarcinoma cell lines. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating choriocarcinoma, with a special focus on preclinical studies.
Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation
Mahmoud L Soliman, Mark D Smith, Heidi M Houdek, Thad A Rosenberger
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-51
Abstract: In this study, we examined the effect of a 28-day-dosing regimen of glyceryl triacetate, to induce acetate supplementation, on brain histone acetylation and interleukin-1β expression in a rat model of lipopolysaccharide-induced neuroinflammation. The effect was analyzed using Western blot analysis, quantitative real-time polymerase chain reaction and enzymic histone deacetylase and histone acetyltransferase assays. Statistical analysis was performed using one-way analysis of variance, parametric or nonparametric when appropriate, followed by Tukey's or Dunn's post-hoc test, respectively.We found that long-term acetate supplementation increased the proportion of brain histone H3 acetylated at lysine 9 (H3K9), histone H4 acetylated at lysine 8 and histone H4 acetylated at lysine 16. However, unlike a single dose of glyceryl triacetate, long-term treatment increased histone acetyltransferase activity and had no effect on histone deacetylase activity, with variable effects on brain histone deacetylase class I and II expression. In agreement with this hypothesis, neuroinflammation reduced the proportion of brain H3K9 acetylation by 50%, which was effectively reversed with acetate supplementation. Further, in rats subjected to lipopolysaccharide-induced neuroinflammation, the pro-inflammatory cytokine interleukin-1β protein and mRNA levels were increased by 1.3- and 10-fold, respectively, and acetate supplementation reduced this expression to control levels.Based on these results, we conclude that dietary acetate supplementation attenuates neuroglial activation by effectively reducing pro-inflammatory cytokine expression by a mechanism that may involve a distinct site-specific pattern of histone acetylation and histone deacetylase expression in the brain.Reversible epigenetic changes play a major role in regulating gene expression in the post-mitotic brain. The most prominent mechanism involved in this process is the alteration in histone acetylation, which is known to in
The histone deacetylase inhibitor trichostatin A induces cell cycle arrest and rapid upregulation of gadd45β in LS174T human colon cancer cells  [PDF]
Tomoyuki Taniguchi, Jun Iwashita, Jun Murata, Kenji Ueda, Tatsuya Abe
Advances in Biological Chemistry (ABC) , 2012, DOI: 10.4236/abc.2012.21005
Abstract: Histone deacetylase (HDAC) inhibitors are considered as promising therapeutic agents against several malignant diseases because they inhibit cancer cell proliferation. The stress sensor genes of the growth arrest and DNA damage-inducible protein (gadd45) family exhibit disordered expression in several types of malignant diseases and are thus a novel target for cancer therapy. However, there have been only few investigations of whether HDAC inhibitors affect the expression of gadd45 genes. We examined the effects of a HDAC inhibitor, trichostatin A (TSA), on the time-dependent expression of gadd45 genes in the human colon cancer cell line LS174T. Addition of TSA to LS174T cells induced inhibition of cell proliferation by arresting the cell cycle. We found that TSA treatment of LS174T cells induced rapid upregulation of gadd45β mRNA expression within 15 min, reaching a peak level at 3 h. Although the time-dependent expression pattern of gadd45β mRNA was similar to that of gadd45β mRNA, the peak level of gadd45β was lower than that of gadd45β. TSA treatment also upregulated the mRNA level of p21Waf1/Cip1, a prolif- eration inhibitor, after 3 h, but downregulated the mRNA levels of cyclin D1, a proliferation inducer, after 3 h, and of c-Myc after 1 h. TSA treatment induced a certain level of apoptosis, but the mRNA level of p53, a potent apoptosis inducer, was down-regulated after 3 h. These results suggest that the up-regulation of p21Waf1/Cip1 and apoptosis was independent of p53 and that the early upregulation of gadd45β gene, which precedes the upregulation of p21Waf1/Cip1 and the downregulation of cyclin D1, are important in TSA-treated LS174T cells.
Overview of Histone Deacetylase Inhibitors in Haematological Malignancies
Mark J. Bishton,Ricky W. Johnstone,Michael Dickinson,Simon Harrison,H. Miles Prince
Pharmaceuticals , 2010, DOI: 10.3390/ph3082674
Abstract: Histone deacetylase inhibitors (HDACi) can induce hyperacetylation of both histone and non-histone target resulting in epigenetic reprogramming and altered activity, stability and localisation of non-histone proteins to ultimately mediate diverse biological effects on cancer cells and their microenvironment. Clinical trials have demonstrated single agent HDACi to have activity in hematological malignancies, in particular T-cell lymphoma and Hodgkin lymphoma. Combination strategies with standard therapies based on pre-clinical data are being employed with significant success due to their excellent side effect profile. Correlative studies will provide valuable information on the sub-groups of patients more likely to respond or be resistant to HDACi therapy, while long-term monitoring for toxicities is also needed.
Experimental in vivo and in vitro treatment with a new histone deacetylase inhibitor belinostat inhibits the growth of pancreatic cancer
Dmitriy I Dovzhanskiy, Stefanie M Arnold, Thilo Hackert, Ina Oehme, Olaf Witt, Klaus Felix, Nathalia Giese, Jens Werner
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-226
Abstract: The proliferation of tumour cell lines (T3M4, AsPC-1 and Panc-1) was determined using an MTT assay. Apoptosis was analysed using flow cytometry. Furthermore, p21Cip1/Waf1 and acetylated histone H4 (acH4) expression were confirmed by immunoblot analysis. The in vivo effect of belinostat was studied in a chimeric mouse model. Antitumoural activity was assessed by immunohistochemistry for Ki-67.Treatment with belinostat resulted in significant in vitro and in vivo growth inhibition of PDAC cells. This was associated with a dose-dependent induction of tumour cell apoptosis. The apoptotic effect of gemcitabine was further enhanced by belinostat. Moreover, treatment with belinostat increased expression of the cell cycle regulator p21Cip1/Waf1 in Panc-1, and of acH4 in all cell lines tested. The reductions in xenograft tumour volumes were associated with inhibition of cell proliferation.Experimental treatment of human PDAC cells with belinostat is effective in vitro and in vivo and may enhance the efficacy of gemcitabine. A consecutive study of belinostat in pancreatic cancer patients alone, and in combination with gemcitabine, could further clarify these effects in the clinical setting.
A conserved histone deacetylase with a role in the regulation of cytokinesis in Schizosaccharomyces pombe
Charnpal Grewal, Jack Hickmott, Stefan Rentas, Jim Karagiannis
Cell Division , 2012, DOI: 10.1186/1747-1028-7-13
Abstract: In this report we identify the hos2 gene as the fission yeast HDAC3 ortholog. We show that Hos2p physically interacts with Set3p, Snt1p, and Hif2p, and that hos2? mutants are indeed compromised in their ability to reliably complete cell division in the presence of mild cytokinetic stresses. Furthermore, we demonstrate that over-expression of hos2 causes severe morphological and cytokinetic defects. Lastly, through recombinase mediated cassette exchange, we show that expression of human HDAC3 complements the cytokinetic defects exhibited by hos2? cells.These data support a model in which Hos2p functions as an essential component of the Set3p-Snt1p-Hif2p complex with respect to the regulation of cytokinesis. The ability of human HDAC3 to complement the cytokinesis defects associated with the deletion of the hos2 gene suggests that further analysis of this system could provide insight into the role of HDAC3 in both the regulation of cell division, as well as other biological processes influenced by HDAC3 deacetylation.In the fission yeast, Schizosaccharomyces pombe, regulatory mechanisms exist to ensure that cytokinesis takes place at the correct spatial location within the cell and at the proper temporal position of the cell cycle [1-5]. The proper spatial positioning of the cytokinetic actomyosin ring is controlled by the anilin-related protein, Mid1p, which - upon entry into mitosis - re-localizes from the nucleus to a medial band defining the future site of cell division [5-9]. The initiation of ring constriction, on the other hand, is signalled by a conserved regulatory module referred to as the Septation Initiation Network (SIN). The SIN is composed of a GTPase signalling cascade that is essential for the temporal co-ordination of cytokinesis, ring constriction, and for the deposition of the division septum [3,5,9,10].In addition to these mechanisms, recent work has also supported the existence of a cytokinesis monitoring system. This system has the capacity to g
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