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Histone Acetylation (histone + acetylation)
Selected AbstractsH4 acetylation does not replace H3 acetylation in chromatin remodelling and transcription activation of Adr1-dependent genesMOLECULAR MICROBIOLOGY, Issue 5 2006Eleonora Agricola Summary Histone acetylation regulates gene expression. Whether this is caused by a general increase in nucleosome fluidity due to charge neutralization or by a more specific code is still matter of debate. By using a set of glucose-repressed Adr1-dependent genes of Saccharomyces cerevisiae, whose transcription was previously shown to require both Gcn5 and Esa1, we asked how changes of histone acetylation patterns at the promoter nucleosomes regulate chromatin remodelling and activation. When the signal of glucose reduction reaches the cells, H4 acetylation is kept constant while an increase of H3 acetylation occurs, in an Adr1- and Gcn5-dependent manner. In cells lacking Gcn5 activity, the H3 acetylation increase does not occur and an unexpected increase of histone H4 acetylation is observed. Nevertheless, chromatin remodelling and transcription activation are impaired, suggesting that acetylation of H3 and H4 histones plays different roles. [source] Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2010Susan E. Bates Summary Romidepsin has shown promise in the treatment of T-cell lymphomas, and so we evaluated molecular endpoints gathered from 61 patients enrolled on a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma at the National Institutes of Health. The endpoints included histone H3 acetylation and ABCB1 gene expression in peripheral blood mononuclear cells (PBMCs); ABCB1 gene expression in tumour biopsy samples; and blood fetal haemoglobin levels (HbF), all of which were increased following romidepsin treatment. The fold increase in histone acetylation in PBMCs at 24 h was weakly to moderately well correlated with the pharmacokinetic parameters Cmax and area under the curve (AUC)last (, = 0·37, P = 0·03 and , = 0·36, P = 0·03 respectively) and inversely associated with clearance (, = ,0·44; P = 0·03). Histone acetylation in PBMCs at 24 h was associated with response (P = 0·026) as was the increase in fetal haemoglobin (P = 0·014); this latter association may be due to the longer on-study duration for patients with disease response. Together, these results suggest that pharmacokinetics may be an important determinant of response to histone deacetylase inhibitors (HDIs) , the association with histone acetylation in PBMCs at 24 h is consistent with a hypothesis that potent HDIs are needed for a critical threshold of drug exposure and durable activity. [source] Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-,1 induced murine tissue inhibitor of metalloproteinases-1 gene expressionFEBS JOURNAL, Issue 8 2005David A. Young Expression of the tissue inhibitor of metalloproteinases-1 (Timp-1) gene can be induced by either phorbol myristate acetate (PMA) or transforming growth factor ,1 (TGF-,1), although the signalling pathways involved are not clearly defined. Canonically, histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) or sodium butyrate (NaB) increase total cellular histone acetylation and activate expression of susceptible genes. Remarkably, PMA and TGF-,1 stimulation of Timp-1 show a differential response to TSA or NaB. TSA or NaB potentiate PMA-induced Timp-1 expression but repress TGF-,1-induced Timp-1 expression. The repression of TGF-,1-induced Timp-1 by TSA was maximal at 5 ng·mL,1, while for the superinduction of PMA-induced Timp-1 expression, the maximal dose is >,500 ng·mL,1 TSA. A further HDACi, valproic acid, did not block TGF-,1-induced Timp-1 expression, demonstrating that different HDACs impact on the induction of Timp-1. For either PMA or TGF-,1 to induce Timp-1 expression, new protein synthesis is required, and the induction of AP-1 factors closely precedes that of Timp-1. The effects of the HDACi can be reiterated in transient transfection using Timp-1 promoter constructs. Mutation or deletion of the AP-1 motif (,59/,53) in the Timp-1 promoter diminishes PMA-induction of reporter constructs, however, the further addition of TSA still superinduces the reporter. In c-Jun,/, cells, PMA still stimulates Timp-1 expression, but TSA superinduction is lost. Transfection of a series of Timp-1 promoter constructs identified three regions through which TSA superinduces PMA-induced Timp-1 and we have demonstrated specific protein binding to two of these regions which contain either an avian erythroblastosis virus E26 (v-ets) oncogene homologue (Ets) or Sp1 binding motif. [source] Expression of mitochondrial HMGCoA synthase and glutaminase in the colonic mucosa is modulated by bacterial speciesFEBS JOURNAL, Issue 1 2004Claire Cherbuy The expression of the colonic mitochondrial 3-hydroxy 3-methyl glutaryl CoA (mHMGCoA) synthase, a key control site of ketogenesis from butyrate, is lower in germ-free (GF) than in conventional (CV) rats. In contrast, the activity of glutaminase is higher. The objective of this study was to investigate whether the intestinal flora can affect gene expression through short chain fatty acid (SCFA) and butyrate production. GF rats were inoculated with a conventional flora (Ino-CV) or with a bacterial strain producing butyrate (Clostridium paraputrificum, Ino- Cp) or not (Bifidobacterium breve, Ino- Bb). In the Ino-CV rats, mHMGCoA synthase expression was restored to the CV values 2 days after the inoculation, i.e. concomitantly with SCFA production. In the Ino- Cp group, but not in the Ino- Bb group, mHMGCoA synthase and glutaminase were expressed at the level observed in the CV rats. These data suggest that the intestinal flora, through butyrate production, could control the expression of colonic mHMGCoA synthase and glutaminase. These modifications in gene expression by butyrate in vivo seem unrelated to a modification of histone acetylation. [source] Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11)GENES, CHROMOSOMES AND CANCER, Issue 4 2003Toshihiko Imamura In this study, we examined a pediatric case of therapy-related myelodysplastic syndrome (tMDS). The symptoms developed 17 months after treatment for acute myeloblastic leukemia (AML, M2 subtype according to the French,American,British [FAB] classification) involving a chromosome abnormality at t(8;21)(q22;q22). Upon diagnosis of tMDS, spectral karyotyping analysis detected a new chromosomal translocation at t(2;8)(p23;p11.2). In addition, fluorescence in situ hybridization analysis suggested a rearrangement in the monocytic leukemia zinc finger (MOZ) gene, located in the 8p11 region of chromosome 8. However, no partner gene on 2p23 could be identified. To our knowledge, this is the first report of tMDS associated with a rearrangement of the MOZ gene. MOZ-linked fusion proteins such as MOZ-CBP (CREB binding protein), MOZ-TIF2 (transcriptional intermediary factor 2), and MOZ-p300 (adenoviral E1A-associated protein) are associated with AML chromosomal abnormalities at t(8;16)(p11;p13), inv(8)(p11q13), and t(8;22)(p11;q13), respectively, and are thought to account for leukemogenesis occurring through the aberrant regulation of histone acetylation. Through a similar mechanism, we believe that MOZ, fused to an unidentified partner gene at 2p23, may have caused an alteration in histone acetylation, resulting in the development of tMDS in this patient. © 2003 Wiley-Liss, Inc. [source] Prognostic significance of the therapeutic targets histone deacetylase 1, 2, 6 and acetylated histone H4 in cutaneous T-cell lymphomaHISTOPATHOLOGY, Issue 3 2008L Marquard Aims:, Aberrant histone acetylation has been associated with malignancy and histone deacetylase (HDAC) inhibitors are currently being investigated in numerous clinical trials. So far, the malignancy most sensitive to HDAC inhibitors has been cutaneous T-cell lymphoma (CTCL). The reason for this sensitivity is unclear and studies on HDAC expression and histone acetylation in CTCL are lacking. The aim of this study was to address this issue. Methods and results:, The immunohistochemical expression of HDAC1, HDAC2, HDAC6, and acetylated H4 was examined in 73 CTCLs and the results related to histological subtypes and overall survival. HDAC1 was most abundantly expressed (P < 0.0001), followed by HDAC2; HDAC6 and H4 acetylation were equally expressed. HDAC2 (P = 0.001) and H4 acetylation (P = 0.03) were significantly more common in aggressive than indolent CTCL subtypes. In contrast, no differences were observed for HDAC1 and HDAC6. In a Cox analysis, elevated HDAC6 was the only parameter showing significant influence on survival (P = 0.04). Conclusions:, High expression of HDAC2 and acetylated H4 is more common in aggressive than indolent CTCL. HDAC6 expression is associated with a favorable outcome independent of the subtype. [source] An interferon-sensitive response element is involved in constitutive caspase-8 gene expression in neuroblastoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2007Alessandro De Ambrosis Abstract We previously identified a 1.2 Kb DNA element (P-1161/+16), 5, to caspase-8 exon-1, that acts as promoter in caspase-8-positive, but not in caspase-8-negative neuroblastoma (NB) cells. The P-1161/+16 DNA element regulates both constitutive and interferon IFN-,-inducible caspase-8 expression. Two GAS (IFN-activated sequence, STAT-1 binding site) and two ISRE (interferon sensitive response element, IRF binding site) were present in P-1161/+16. Deletion studies indicated that elements essential for promoter activity in NB cells were present in a 167 bp region 5, flanking exon-1 (P-151/+16), which contains an ISRE at position ,32. The transcription initiation site was mapped by 5, rapid amplification of cDNA end (RACE) at position ,20 from caspase-8 cDNA reference sequence. Disruption of the ISRE-32 indicated that it is required for both constitutive and IFN-,-inducible caspase-8 expression. IRF-1 and IRF-2 transcription factors bind to the (,151/+16) DNA fragment in vitro. Chromatin immunoprecipitation (ChIP) assays showed that IRF-1 and IRF-2 bind to the DNA region at the 5, of caspase-8 gene in NB cells, which show constitutive expression but not in caspase-8 negative cells. In these last cells, up-regulation of caspase-8 by IFN-, was associated to induction of IRF-1 and IRF-2 binding to caspase-8 promoter and increased histone acetylation. Moreover, RNA interference experiments also supported the involvement of IRF-1 and IRF-2 in constitutive caspase-8 expression in NB cells. © 2006 Wiley-Liss, Inc. [source] Chronic administration of valproic acid inhibits PC3 cell growth by suppressing tumor angiogenesis in vivoINTERNATIONAL JOURNAL OF UROLOGY, Issue 9 2007Dexuan Gao Aim: Chromatin remodeling agents such as histone deacetylase inhibitors have been shown to modulate gene expression in tumor cells and inhibit tumor growth and angiogenesis. We investigated the mechanisms of chronic valproic acid (VPA) inhibiting PC3 cell growth in the study. Methods: We established tumor xenografts of the PC3 cell line and investigated the effect of VPA chronic administration on tumor growth. Apoptosis in tumor tissue was measured using the TUNEL Detection Kit. We detected the effect of VPA chronic administration on histone acetylation; p21CIP1/WAF1 gene expression; vascular endothelial growth factor (VEGF) expression by reverse-transcription Polymerase Chain Reaction (PCR) analysis; immunohistochemistry; and Western Blotting. Result: In mouse models with established subcutaneous prostate (PC3), VPA treatment induced 70% inhibition of tumor growth without overt toxicity. Our result showed that chronic administration of VPA has an effect on tumor growth arrest and the effect was associated with increased histone acetylation, p21CIP1/WAF1 up-regulation, and VEGF down-regulation. Conclusion: We conclude that chronic VPA results in profound decreases in the proliferation of PC3 cells, not only by increasing histone H3 acetylation and up-regulating p21CIP1/WAF1 expression, but also by down-regulating VEGF. [source] Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesisJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6b 2008Ian Buysschaert ,,Introduction ,,Angiogenesis is genetically pre-determined ,,Mutations causing vascular anomalies -,Venous anomalies -,Haemangiomas -,The transforming growth factor-ß in vascular anomalies -,Cerebral cavernous malformations ,,Translocations reveal novel angiogenic genes ,,Single nucleotide polymorphisms shape the angio-genome -,SNPs in VEGF and their association with cancer -,SNPs in VEGF pathway genes associated with other diseases -,Genetic variability in VEGFR-2 -,Genetic variability in HIF-1, -,SNPs in VEGFR-1 integrate angiogenesis within the P53 pathway -,Variations in angiogenic genes are linked with neurodegeneration -,Angiogenic factors in genome-wide association studies ,,Copy number variability affects angiogenesis ,,Epigenetic regulation of angiogenesis -,Methylation of anti-angiogenic factors -,Methylation as a second hit event in cancer -,Histone modifications determine angiogenesis ,,Micromanagers of angiogenesis ,,Perspectives Abstract Angiogenesis is controlled by a balance between pro- and anti-angiogenic factors. Studies in mice and human beings have shown that this balance, as well as the general sensitivity of the endothelium to these factors, is genetically pre-determined. In an effort to dissect this genetic basis, different types of genetic variability have emerged: mutations and translocations in angiogenic factors have been linked to several vascular malformations and haemangiomas, whereas SNPs have been associated with complex genetic disorders, such as cancer, neurodegeneration and diabetes. In addition, copy number alterations of angiogenic factors have been reported in several tumours. More recently, epigenetic changes caused by aberrant DNA methylation or histone acetylation of anti-angiogenic molecules have been shown to determine angiogenesis as well. Initial studies also revealed a crucial role for microRNAs in stimulating or reducing angiogenesis. So far, most of these genetic studies have focused on tumour angiogenesis, but future research is expected to improve our understanding of how genetic variants determine angiogenesis in other diseases. Importantly, these genetic insights might also be of important clinical relevance for the use of anti-angiogenic strategies in cancer or macular degeneration. [source] Interconversion of intra- and extra-chromosomal sites of gene amplification by modulation of gene expression and DNA methylationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2007Noriaki Shimizu Abstract We previously showed that plasmids containing a mammalian replication initiation region and a matrix attachment region were efficiently amplified to few thousand copies per cell, and that they formed extrachromosomal double minutes (DMs) or chromosomal homogeneously staining regions (HSRs). In these structures, the plasmid sequence was arranged as a tandem repeats, and we suggested a mechanism of plasmid amplification. Since amplification was very efficient, easy, and convenient, it might be adapted to a novel method for protein production. In the current study, we found that gene expression from the tandem plasmid repeat was suppressed. We identified several strategies to overcome this suppression, including: (1) use of higher concentrations of antibiotic during cell selection; (2) treatment of cells with agents that influence DNA methylation (5-azacytidine) or histone acetylation (butyrate); (3) co-amplification of an insulator sequence; and (4) co-amplification of sequences that encode a transcriptional activator. Expression from the plasmid repeat was always higher at DMs compared to HSRs. We found that continuous activation of a plasmid-encoded inducible promoter prevented the generation of long HSRs, and favored amplification at DMs. Consistent with this finding, there was a synergistic effect of transcriptional activation and inhibition of DNA methylation on the fragmentation of long HSRs and the generation of DMs and short HSRs. Our results indicate that both transcriptional activation and DNA methylation regulate the interconversion between extra- and intra-chromosomal gene amplification. These results have important implications for both protein production technology, and the generation of chromosomal abnormalities found in human cancer cells. J. Cell. Biochem. 102: 515,529, 2007. © 2007 Wiley-Liss, Inc. [source] Epigenetics are involved in the regulation of the cell cycle and expression of tumor suppressor genes in human colon cancer cellsJOURNAL OF DIGESTIVE DISEASES, Issue 3 2003Ying Xuan CHEN OBJECTIVE: To investigate the effects of DNA methylation and histone acetylation on the cell cycle progression and expression of tumor suppressor genes in human colon cancer (HCC) cell lines. METHODS: Three HCC cell lines (HT-29, SW1116 and Colo-320) were treated with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC) or/and histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) or sodium butyrate. The methylation status of the promoter of the p16INK4A gene was assayed by methylation-specific PCR (MSP). The expression of p16INK4A and p21WAF1 was analyzed by RT-PCR. The cell cycle distribution was determined by flow cytometry. RESULTS: Before treatment, p16INK4A expression was slightly detected in the three cell lines (HT-29, SW1116 and Colo-320) and p21WAF1 expression was not detected in SW1116 and Colo-320 cells. The methylation level of the p16INK4A gene promoter significantly decreased and mRNA expression markedly increased in HT-29 cells after treatment with 1 µmol/L, but not 10 µmol/L, of 5-aza-dC for 24 h. In the SW1116 and Colo-320 cells, the expression of p16INK4A was markedly enhanced at 10 µmol/L or 5 µmol/L of 5-aza-dC for 24 h. However, p21WAF1 gene expression was not detected. Interestingly, after treatment with TSA or sodium butyrate, the transcription of p21WAF1 was significantly upregulated in these two cell lines. Furthermore, 5-aza-dC did not affect cell cycle distribution, but TSA or sodium butyrate blocked the cell cycle, mainly in the G1 phase. CONCLUSIONS: The expression of the p16INK4A gene is regulated by DNA methylation in three HCC cell lines. The expression of p21WAF1 gene is regulated by histone acetylation in SW1116 and Colo-320. In these two cell lines, histone hyperacetylation causes a G1 cell cycle arrest. [source] EFFECT OF BUTYRIC ACID SUPPLEMENTATION ON SERUM AND RENAL ANTIOXIDANT ENZYME ACTIVITIES IN STREPTOZOTOCIN-INDUCED DIABETIC RATSJOURNAL OF FOOD BIOCHEMISTRY, Issue 2010A. PUNEETH KUMAR ABSTRACT Reactive oxygen metabolites, which are constant products of normal aerobic cell metabolism, play a key role in worsening the pathophysiological complications of diabetes. The present investigation was aimed at understanding the effect of butyric acid supplementation along with wheatbran and guar gum on serum and renal antioxidant enzyme activities and lipid peroxidation in streptozotocin (STZ)-induced diabetic rats. Activities of superoxide dismutase, catalase, glutathione peroxidase were evaluated in serum and kidney of control and experimental rats. Results clearly showed that the altered activity of the enzymes during diabetes was significantly ameliorated by butyric acid (500 mg/kg body weight/day) supplementation compared with other experimental groups. Further, the increased lipid peroxidation in serum and kidney of diabetic rats was also significantly reduced in butyric acid-supplemented diabetic rats. The study led us to conclude that butyric acid exert antioxidant property, thereby minimizing oxidative stress induced diabetes and its related complications. PRACTICAL APPLICATIONS Butyric acid , a product of dietary fiber fermentation , is a four-carbon fatty acid, which has wide range of application in disease management. This product is involved in various physiological functions of body like cell differentiation, apoptosis, colonic homeostasis, histone acetylation, etc. It is also known to decrease the incidence of bowel cancer and some of its analogues are shown to selectively improve glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. This study aims to evaluate the beneficial effects of butyric acid supplementation on oxidative stress-induced diabetic complications in rats. [source] Sp proteins play a critical role in histone deacetylase inhibitor-mediated derepression of CYP46A1 gene transcriptionJOURNAL OF NEUROCHEMISTRY, Issue 2 2010Maria Joćo Nunes J. Neurochem. (2010) 113, 418,431. Abstract We investigated whether the CYP46A1 gene, a neuronal-specific cytochrome P450, responsible for the majority of brain cholesterol turnover, is subject to transcriptional modulation through modifications in histone acetylation. We demonstrated that inhibition of histone deacetylase activity by trichostatin A (TSA), valproic acid and sodium butyrate caused a potent induction of both CYP46A1 promoter activity and endogenous expression. Silencing of Sp transcription factors through specific small interfering RNAs, or impairing Sp binding to the proximal promoter, by site-directed mutagenesis, led to a significant decrease in TSA-mediated induction of CYP46A1 expression/promoter activity. Electrophoretic mobility shift assay, DNA affinity precipitation assays and chromatin immunoprecipitation assays were used to determine the multiprotein complex recruited to the CYP46A1 promoter, upon TSA treatment. Our data showed that a decrease in Sp3 binding at particular responsive elements, can shift the Sp1/Sp3/Sp4 ratio, and favor the detachment of histone deacetylase (HDAC) 1 and HDAC2 and the recruitment of p300/CBP. Moreover, we observed a dynamic change in the chromatin structure upon TSA treatment, characterized by an increase in the local recruitment of euchromatic markers and RNA polymerase II. Our results show the critical participation of an epigenetic program in the control of CYP46A1 gene transcription, and suggest that brain cholesterol catabolism may be affected upon treatment with HDAC inhibitors. [source] Silent mysteries: epigenetic paradigms could hold the key to conquering the epidemic of allergy and immune diseaseALLERGY, Issue 1 2010D. J. Martino Abstract Epigenetic mechanisms provide new insights into how environmental changes may mediate the increasing propensity for complex immune diseases such as allergic disease. There is now strong evidence that early environmental exposures play a key role in activating or silencing genes by altering DNA and histone methylation, histone acetylation and chromatin structure. These modifications determine the degree of DNA compaction and accessibility for gene transcription, altering gene expression, phenotype and disease susceptibility. While there is already evidence that a number of early environmental exposures are associated with an increased risk of allergic disease, several new studies indicate in utero microbial and dietary exposures can modify gene expression and allergic disease propensity through epigenetic modification. This review explores the evidence that immune development is under clear epigenetic regulation, including the pattern of T helper (Th)1 and Th2 cell differentiation, regulatory T cell differentiation, and more recently, Th17 development. It also considers the mechanisms of epigenetic regulation and early immune defects in allergy prone neonates. The inherent plasticity conferred by epigenetic mechanisms clearly also provides opportunities for environmental strategies that can re-programme gene expression for disease prevention. Identifying genes that are differentially silenced or activated in relation to subsequent disease will not only assist in identifying causal pathways, but may also help identify the contributing environmental factors. [source] Electron microscopy analysis of histone acetylation and DNA strand breaks in mouse elongating spermatids using a dual labelling approachANDROLOGIA, Issue 5 2010G. Bikond Nkoma Summary Chromatin remodelling steps in mammalian spermatids include post-translational modifications of histones and DNA fragmentation. Histone H4 hyperacetylation (AcH4) establishes a chromatin state that facilitates DNA repair in somatic cells. So we sought to determine whether a similar link exists in spermatids by combining immunogold labelling with detection of DNA strand breaks, making use of gold particles of different sizes. DNA strand breaks were not detected in the vicinity of AcH4 chromatin, suggesting that this modified histone may not be involved in the aetiology of DNA fragmentation and repair in spermatids. The AcH4 reactivity, however, indicates that chromatin remodelling is distributed throughout the nucleus. [source] Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle diseaseARTHRITIS & RHEUMATISM, Issue 8 2003Satoshi Okada Objective To determine if geoclimatic factors may influence the nature and frequency of dermatomyositis (DM), polymyositis, and associated autoantibodies around the world. Methods We assessed, in the first global evaluation of these conditions, the relationship between 13 geoclimatic variables that may modulate disease and the relative proportion of DM and its associated autoantibody anti,Mi-2, directed against an SNF2-superfamily helicase associated with the nucleosome remodeling and histone acetylation and deacetylation complex, in a global myositis population. Altogether, 919 consecutive patients from populations at 15 locations were studied. Results Univariate and multivariate analyses demonstrated that of the variables evaluated, surface ultraviolet (UV) radiation intensity (irradiance) most strongly contributed to the relative proportion of DM and was strongly related to the proportion of anti,Mi-2 autoantibodies (weighted r = 0.939, P < 4 × 10 -7 and weighted r = 0.69, P = 0.02, respectively). Published ethnogeographic immunogenetic allele frequencies imply that the striking differences in the proportion of DM- and DM-specific autoantibodies observed around the world are not the result of inherent global variations in known genetic risk factors. Conclusion These data suggest that UV radiation exposure may modulate the clinical and immunologic expression of an autoimmune disease in different populations around the world. [source] A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2010Tapan M. Kadia Summary Histone deacetylase inhibitors (HDACi) affect chromatin remodelling and modulate the expression of aberrantly silenced genes. HDACi have single-agent clinical activity in haematological malignancies and have synergistic anti-leukaemia activity when combined with anthracyclines in vitro. We conducted a two-arm, parallel Phase I trial to investigate two schedules of escalating doses of vorinostat (Schedule A: thrice daily (TID) for 14 d; B: TID for 3 d) in combination with a fixed dose of idarubicin in patients with refractory leukaemia. Of the 41 patients enrolled, 90% had acute myeloid leukaemia, with a median of 3 prior therapies. Seven responses (17%) were documented (two complete response (5%), one complete response without platelet recovery (2·5%), and four marrow responses). The 3-d schedule of vorinostat was better tolerated than the 14-d schedule. The maximum tolerated dose for vorinostat was defined as 400 mg TID for 3 d. The most common grade 3 and 4 toxicities included mucositis, fatigue and diarrhoea. Correlative studies demonstrated histone acetylation in patients on therapy and modulation of CDKN1A and TOP2A (topoisomerase II) gene expression. Pharmacokinetic analysis confirmed a dose-related elevation in plasma vorinostat concentrations. The combination of vorinostat and idarubicin is generally tolerable and active in patients with advanced leukaemia and should be studied in the front-line setting. [source] Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2010Susan E. Bates Summary Romidepsin has shown promise in the treatment of T-cell lymphomas, and so we evaluated molecular endpoints gathered from 61 patients enrolled on a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma at the National Institutes of Health. The endpoints included histone H3 acetylation and ABCB1 gene expression in peripheral blood mononuclear cells (PBMCs); ABCB1 gene expression in tumour biopsy samples; and blood fetal haemoglobin levels (HbF), all of which were increased following romidepsin treatment. The fold increase in histone acetylation in PBMCs at 24 h was weakly to moderately well correlated with the pharmacokinetic parameters Cmax and area under the curve (AUC)last (, = 0·37, P = 0·03 and , = 0·36, P = 0·03 respectively) and inversely associated with clearance (, = ,0·44; P = 0·03). Histone acetylation in PBMCs at 24 h was associated with response (P = 0·026) as was the increase in fetal haemoglobin (P = 0·014); this latter association may be due to the longer on-study duration for patients with disease response. Together, these results suggest that pharmacokinetics may be an important determinant of response to histone deacetylase inhibitors (HDIs) , the association with histone acetylation in PBMCs at 24 h is consistent with a hypothesis that potent HDIs are needed for a critical threshold of drug exposure and durable activity. [source] Histones and histone modifications in protozoan parasitesCELLULAR MICROBIOLOGY, Issue 12 2006William J. Sullivan Jr Summary Protozoan parasites are early branching eukaryotes causing significant morbidity and mortality in humans and livestock. Single-celled parasites have evolved complex life cycles, which may involve multiple host organisms, and strategies to evade host immune responses. Consequently, two key aspects of virulence that underlie pathogenesis are parasite differentiation and antigenic variation, both of which require changes in the expressed genome. Complicating these requisite alterations in the parasite transcriptome is chromatin, which serves as a formidable barrier to DNA processes including transcription, repair, replication and recombination. Considerable progress has been made in the study of chromatin dynamics in other eukaryotes, and there is much to be gained in extending these analyses to protozoan parasites. Much of the work completed to date has focused on histone acetylation and methylation in the apicomplexans and trypanosomatids. As we describe in this review, such studies provide a unique vantage point of the evolutionary picture of eukaryotic cell development, and reveal unique phenomena that could be exploited pharmacologically to treat protozoal diseases. [source] Searching for Disease Modifiers,PKC Activation and HDAC Inhibition,A Dual Drug Approach to Alzheimer's Disease that Decreases A, Production while Blocking Oxidative StressCHEMMEDCHEM, Issue 7 2009Abstract A series of benzolactam compounds were synthesized, some of which caused a concentration-dependent increase in sAPP, and decrease in A, production in the concentration range of 0.1,10,,M. Moreover, some compounds showed neuroprotective effects in the 10,20,,M range in the HCA cortical neuron model of oxidative stress and no toxicity in measurements of neuron viability by MTT assay, even at the highest concentrations tested (20,,M). Alzheimer's disease (AD) is a well-studied neurodegenerative process characterized by the presence of amyloid plaques and neurofibrillary tangles. In this study, a series of protein kinase,C (PKC) activators were investigated, some of which also exhibit histone deacetylase (HDAC) inhibitory activity, under the hypothesis that such compounds might provide a new path forward in the discovery of drugs for the treatment of AD. The PKC-activating properties of these drugs were expected to enhance the ,-secretase pathway in the processing of amyloid precursor protein (APP), while their HDAC inhibition was anticipated to confer neuroprotective activity. We found that benzolactams 9 and 11,14 caused a concentration-dependent increase in sAPP, and decrease in ,-amyloid (A,) production in the concentration range of 0.1,10,,M, consistent with a shift of APP metabolism toward the ,-secretase-processing pathway. Moreover, compounds 9,14 showed neuroprotective effects in the 10,20,,M range in the homocysteate (HCA) cortical neuron model of oxidative stress. In parallel, we found that the most neuroprotective compounds caused increased levels of histone acetylation (H4), thus indicating their likely ability to inhibit HDAC activity. As the majority of the compounds studied also show nanomolar binding affinities for PKC, we conclude that it is possible to design, de,novo, agents that combine both PKC-activating properties along with HDAC inhibitory properties. Such agents would be capable of modulating amyloid processing while showing neuroprotection. These findings may offer a new approach to therapies that exhibit disease-modifying effects, as opposed to symptomatic relief, in the treatment of AD. [source] Suppression of lipopolysaccharide- and tumour necrosis factor-,-induced interleukin (IL)-8 expression by glucocorticoids involves changes in IL-8 promoter acetylationCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2007L. G. Tsaprouni Summary There is accumulating evidence that the transrepressional effect of glucocorticoids in down-regulating proinflammatory gene expression might be regulated by an action on histone acetylation. To investigate this, we studied the effect of two glucocorticoids (dexamethasone and triamcinolone acetonide) on reducing lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-,-induced interleukin (IL)-8 release in a monocytic cell line and two lymphocytic cell lines (HUT-78 and Jurkat). The effect of the histone deacetylase inhibitor trichostatin A (TSA) on LPS- and TNF-,-induced IL-8 release and its repression by glucocorticoids was also examined. LPS and TNF-, induced IL-8 release in all three cell lines and this induction was inhibited by both dexamethasone and triamcinolone. Pretreatment of cells with TSA enhanced basal and LPS- and TNF,-stimulated IL-8 release in all three cell lines. TSA also attenuated the inhibitory effect of glucocorticoids on stimulated IL-8 release. Chromatin immunoprecipitation assays confirmed that LPS and TNF-, enhanced histone acetylation at the IL-8 promoter and that this was inhibited by triamcinolone in all three cell types. Changes in histone acetylation at the IL-8 are important in its regulation by proinflammatory and anti-inflammatory agents, and modulation of this activity may have therapeutic potential in inflammatory conditions. [source] | ||||||||||||||||