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The Journal of Pathology. Clinical... Apr 2016Histone deacetylases (HDAC) are key players in epigenetic regulation of gene expression and HDAC inhibitor (HDACi) treatment seems to be a promising anticancer therapy...
Histone deacetylases (HDAC) are key players in epigenetic regulation of gene expression and HDAC inhibitor (HDACi) treatment seems to be a promising anticancer therapy in many human tumours, including soft tissue sarcomas. HR23b has been shown to be a potential biomarker for sensitivity to HDACi therapy in cutaneous T-cell lymphoma and hepatocellular carcinoma. We aimed to evaluate HR23b as a candidate biomarker for HDACi response in sarcomas and gastrointestinal stromal tumours (GIST). Therefore, HR23b expression was analysed comprehensively by western blot in sarcoma and GIST cell lines covering all major clinically relevant subtypes. MTT assay and ApoTox-Glo(TM) Triplex assay were performed after treatment with vorinostat, belinostat, mocetinostat and entinostat. HR23b protein expression was measured under HDACi treatment. Furthermore, HR23b expression levels were immunohistochemically determined in a large set of 523 clinical samples from sarcoma and GIST patients. Western blot analyses showed that sarcomas differ significantly in their expression of HR23b protein. All HDACi were able to regulate proliferation and apoptosis in vitro. Sensitivity to vorinostat correlated significantly with HR23b protein expression. Immunohistochemical prevalence screening in clinical samples of relevant adult-type tumours revealed that 12.5% of sarcomas (among them malignant peripheral nerve sheath tumours, pleomorphic liposarcomas, leiomyosarcomas, dedifferentiated liposarcomas, synovial sarcomas and angiosarcomas) and 23.2% of GIST show high HR23b expression. Therefore, HDACi have antiproliferative and proapoptotic effects in sarcomas depending on the expression level of HR23b. These findings suggest that HR23b represents a candidate biomarker for HDACi sensitivity in certain sarcoma types and in GIST.
PubMed: 27499916
DOI: 10.1002/cjp2.35 -
CNS Neuroscience & Therapeutics Feb 2019Recently, histone deacetylase (HDAC) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease (AD). However, HDACi treatments exhibit diverse...
AIMS
Recently, histone deacetylase (HDAC) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease (AD). However, HDACi treatments exhibit diverse functions with unfavorable effects in AD. Thus, the development of selective HDACi without side effects is urgently needed.
METHODS
HDACi, namely, BML210, MGCD0103, PXD101, and Droxinostat, were screened in mouse hippocampal primary cultures incubated with oligomeric Aβ (50 μmol/L). MGCD0103 was chosen for in vivo tests and was intraperitoneally injected into C57BL/6J mice (0.5 mg/kg, once per day) for 4 weeks following an intrahippocampal CA1 injection of oligomeric Aβ . Brain samples were collected for pathological analyses after the behavioral analyses including open- field test (OFT), elevated plus maze (EPM), Y-maze, and Morris water maze (MWM).
RESULTS
Among the HDACi, MGCD0103 exhibited significant neuroprotection against the Aβ toxicity in primary cultures. MGCD0103 coattenuated cognitive deficits and anxiety against Aβ damage in mice. MGCD0103 further ameliorated pathological features such as the levels of acetylated histone 3 at Lys 9 site (H3K9) and α-tubulin, synaptophysin, Aβ, tau protein phosphorylation, and serotonergic neuron loss against Aβ toxicity. Furthermore, chronic MGCD0103 treatment did not show liver or kidney toxicity in mice.
CONCLUSIONS
These results reveal MGCD0103 could be a potential therapeutic agent against AD.
Topics: Amyloid beta-Peptides; Animals; Anxiety; Behavior, Animal; Benzamides; CA1 Region, Hippocampal; Cognitive Dysfunction; Female; Hippocampus; Histone Deacetylase Inhibitors; Male; Maze Learning; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Peptide Fragments; Primary Cell Culture; Pyrimidines
PubMed: 29978554
DOI: 10.1111/cns.13029 -
Circulation Research Mar 2012Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the...
RATIONALE
Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with associated right ventricular cardiac remodeling are poorly understood.
OBJECTIVE
This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension.
METHODS AND RESULTS
Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression.
CONCLUSIONS
By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for pulmonary hypertension that will complement vasodilator standards of care.
Topics: Animals; Benzamides; Blood Pressure; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Heart Ventricles; Histone Deacetylase Inhibitors; Histone Deacetylases; Hypertension, Pulmonary; Hypoxia; Muscle, Smooth, Vascular; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Ventricular Remodeling
PubMed: 22282194
DOI: 10.1161/CIRCRESAHA.111.258426 -
Oncotarget Jul 2016Histone deacetylases (HDACs) play crucial roles in the initiation and progression of cancer, offering a promising target for cancer therapy. HDACs inhibitor MGCD0103...
Histone deacetylases (HDACs) play crucial roles in the initiation and progression of cancer, offering a promising target for cancer therapy. HDACs inhibitor MGCD0103 (MGCD) exhibits effective anti-tumor activity by blocking proliferation and inducing cell death in malignant cells. However, the molecular mechanisms of HDACs inhibition induces cell death have not been well elucidated. In this study, we showed that MGCD effectively restored histone acetylation, suppressed cell growth and induced apoptosis in two-dimensional (2D) and three-dimensional (3D) cultured CNE1 and CNE2 nasopharyngeal carcinoma (NPC) cells. Importantly, MGCD arrested cell cycle at mitosis (M) phase with formation of multipolar spindles, which was associated with activated p53-mediated postmitotic checkpoint pathway to induce apoptotic cell death. Moreover, MGCD-induced apoptosis was decreased by inhibition of p53 using short interfering RNA (siRNA), suggesting that p53 was required for MGCD-induced cell apoptosis. Consistently, MGCD in combination with Nutlin-3, a MDM2 inhibitor showed synergistic effect on inducing apoptosis in 2D and 3D cultured CNE2 cells. Collectively, our data revealed that MGCD induced p53-dependent cell apoptosis following formation of multipolar spindles in NPC cells, suggesting the therapeutic potential of combinations of HDACs and MDM2 inhibitors for NPC treatment.
Topics: Acetylation; Apoptosis; Benzamides; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; M Phase Cell Cycle Checkpoints; Nasopharyngeal Neoplasms; Pyrimidines; RNA Interference; Spindle Apparatus; Tumor Suppressor Protein p53
PubMed: 27283770
DOI: 10.18632/oncotarget.9922 -
Cancer Science Jun 2011Histone deacetylase inhibitors are a group of recently developed compounds that modulate cell growth and survival. We evaluated the effects of the histone deacetylase...
Histone deacetylase inhibitors are a group of recently developed compounds that modulate cell growth and survival. We evaluated the effects of the histone deacetylase inhibitor MGCD0103 on growth of pancreatic carcinoma models following single agent treatment and in combination with gemcitabine. MGCD0103 inhibited tumor cell growth and acted synergistically with gemcitabine to enhance its cytotoxic effects. Gene expression analysis identified the cell cycle pathway as one of the most highly modulated gene groups. Our data suggest that MGCD0103 + gemcitabine might be an effective treatment for gemcitabine-refractory pancreatic cancer.
Topics: Apoptosis; Benzamides; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Drug Synergism; Gene Expression; Histone Deacetylase Inhibitors; Humans; Immunoblotting; Pancreas; Pancreatic Neoplasms; Pyrimidines; Gemcitabine
PubMed: 21375679
DOI: 10.1111/j.1349-7006.2011.01921.x -
Clinical Cancer Research : An Official... Jun 2008The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel...
PURPOSE
The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel whole-cell HDAC enzyme assay.
EXPERIMENTAL DESIGN
Boc-Lys(epsilon-Ac)-AMC, a HDAC substrate with fluorescent readout, was found to be cell permeable and was used to monitor MGCD0103-mediated HDAC inhibition in cultured cancer cells in vitro, in peripheral WBC ex vivo, in mice in vivo, and in human patients.
RESULTS
MGCD0103 inhibited HDAC activity in several human cancer cell lines in vitro and in human peripheral WBC ex vivo in a dose-dependent manner. Unlike suberoylanilide hydroxamic acid, the HDAC inhibitory activity of MGCD0103 was time dependent and sustained for at least 24 hours following drug removal in peripheral WBC ex vivo. Inhibitory activity of MGCD0103 was sustained for at least 8 hours in vivo in mice and 48 hours in patients with solid tumors. HDAC inhibitory activity of MGCD0103 in peripheral WBC correlated with induction of histone acetylation in blood and in implanted tumors in mice. In cancer patients, sustained pharmacodynamic effect of MGCD0103 was visualized only by dose-dependent enzyme inhibition in peripheral WBC but not by histone acetylation analysis.
CONCLUSIONS
This study shows that MGCD0103 has sustained pharmacodynamic effects that can be monitored both in vitro and in vivo with a cell-based HDAC enzyme assay.
Topics: Animals; Antineoplastic Agents; Benzamides; Biological Assay; Cell Line, Tumor; Drug Administration Schedule; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Inhibitory Concentration 50; Mice; Neoplasms; Pyrimidines; Xenograft Model Antitumor Assays
PubMed: 18519775
DOI: 10.1158/1078-0432.CCR-07-4427 -
Stem Cells Translational Medicine Sep 2015Cardiac c-Kit+ cells have a modest cardiogenic potential that could limit their efficacy in heart disease treatment. The present study was designed to augment the...
UNLABELLED
Cardiac c-Kit+ cells have a modest cardiogenic potential that could limit their efficacy in heart disease treatment. The present study was designed to augment the cardiogenic potential of cardiac c-Kit+ cells through class I histone deacetylase (HDAC) inhibition and evaluate their therapeutic potency in the chronic heart failure (CHF) animal model. Myocardial infarction (MI) was created by coronary artery occlusion in rats. c-Kit+ cells were treated with mocetinostat (MOCE), a specific class I HDAC inhibitor. At 3 weeks after MI, CHF animals were retrogradely infused with untreated (control) or MOCE-treated c-Kit+ cells (MOCE/c-Kit+ cells) and evaluated at 3 weeks after cell infusion. We found that class I HDAC inhibition in c-Kit+ cells elevated the level of acetylated histone H3 (AcH3) and increased AcH3 levels in the promoter regions of pluripotent and cardiac-specific genes. Epigenetic changes were accompanied by increased expression of cardiac-specific markers. Transplantation of CHF rats with either control or MOCE/c-Kit+ cells resulted in an improvement in cardiac function, retardation of CHF remodeling made evident by increased vascularization and scar size, and cardiomyocyte hypertrophy reduction. Compared with CHF infused with control cells, infusion of MOCE/c-Kit+ cells resulted in a further reduction in left ventricle end-diastolic pressure and total collagen and an increase in interleukin-6 expression. The low engraftment of infused cells suggests that paracrine effects might account for the beneficial effects of c-Kit+ cells in CHF. In conclusion, selective inhibition of class I HDACs induced expression of cardiac markers in c-Kit+ cells and partially augmented the efficacy of these cells for CHF repair.
SIGNIFICANCE
The study has shown that selective class 1 histone deacetylase inhibition is sufficient to redirect c-Kit+ cells toward a cardiac fate. Epigenetically modified c-Kit+ cells improved contractile function and retarded remodeling of the congestive heart failure heart. This study provides new insights into the efficacy of cardiac c-Kit+ cells in the ischemic heart failure model.
Topics: Acetylation; Animals; Benzamides; Biomarkers; Cell Differentiation; Cells, Cultured; Collagen; Disease Models, Animal; Epigenesis, Genetic; Heart Failure; Histone Deacetylase Inhibitors; Histones; Interleukin-6; Male; Myocardial Infarction; Myocytes, Cardiac; Pluripotent Stem Cells; Proto-Oncogene Proteins c-kit; Pyrimidines; Rats; Rats, Sprague-Dawley; Recovery of Function; Tissue Culture Techniques; Ventricular Function, Left; Ventricular Remodeling
PubMed: 26240433
DOI: 10.5966/sctm.2014-0290 -
Sheng Li Xue Bao : [Acta Physiologica... Oct 2015To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors,...
Selective class I histone deacetylase inhibitors suppress persistent spontaneous nociception and thermal hypersensitivity in a rat model of bee venom-induced inflammatory pain.
To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.
Topics: Animals; Bee Venoms; Benzamides; Epigenesis, Genetic; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Hot Temperature; Hyperalgesia; Inflammation; Injections, Subcutaneous; Nociception; Pain; Pain Measurement; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Up-Regulation
PubMed: 26490061
DOI: No ID Found -
Cell Death Discovery 2016Epithelial-mesenchymal transition (EMT), a crucial mechanism in development, mediates aggressiveness during carcinoma progression and therapeutic refractoriness. The...
An epithelial marker promoter induction screen identifies histone deacetylase inhibitors to restore epithelial differentiation and abolishes anchorage independence growth in cancers.
Epithelial-mesenchymal transition (EMT), a crucial mechanism in development, mediates aggressiveness during carcinoma progression and therapeutic refractoriness. The reversibility of EMT makes it an attractive strategy in designing novel therapeutic approaches. Therefore, drug discovery pipelines for EMT reversal are in need to discover emerging classes of compounds. Here, we outline a pre-clinical drug screening platform for EMT reversal that consists of three phases of drug discovery and validation. From the Phase 1 epithelial marker promoter induction (EpI) screen on a library consisting of compounds being approved by Food and Drug Administration (FDA), Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), is identified to exert EMT reversal effects by restoring the expression of an epithelial marker, E-cadherin. An expanded screen on 41 HDACi further identifies 28 compounds, such as class I-specific HDACi Mocetinosat, Entinostat and CI994, to restore E-cadherin and ErbB3 expressions in ovarian, pancreatic and bladder carcinoma cells. Mocetinostat is the most potent HDACi to restore epithelial differentiation with the lowest concentration required for 50% induction of epithelial promoter activity (EpIC-50).The HDACi exerts paradoxical effects on EMT transcriptional factors such as SNAI and ZEB family and the effects are context-dependent in epithelial- and mesenchymal-like cells. In vitro functional studies further show that HDACi induced significant increase in anoikis and decrease in spheroid formation in ovarian and bladder carcinoma cells with mesenchymal features. This study demonstrates a robust drug screening pipeline for the discovery of compounds capable of restoring epithelial differentiation that lead to significant functional lethality.
PubMed: 27551531
DOI: 10.1038/cddiscovery.2016.41 -
Journal of Clinical Oncology : Official... Apr 2008MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth...
PURPOSE
MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth control in malignancies.
PATIENTS AND METHODS
A phase I trial of MGCD0103, given as a three-times-per-week oral dose for 2 of every 3 weeks, was performed in patients with advanced solid tumors. Primary end points were safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity, and histone acetylation status in peripheral WBCs.
RESULTS
Six dose levels ranging from 12.5 to 56 mg/m(2)/d were evaluated in 38 patients over 99 cycles (median, 2; range, 1 to 11). The recommended phase II dose was 45 mg/m(2)/d. Dose-limiting toxicities consisting of fatigue, nausea, vomiting, anorexia, and dehydration were observed in three (27%) of 11 and two (67%) of three patients treated at the 45 and 56 mg/m(2)/d dose levels, respectively. Disease stabilization for four or more cycles was observed in five (16%) of 32 patients assessable for efficacy. PK analyses demonstrated interpatient variability which was improved by coadministration with low pH beverages. Elimination half-life ranged from 6.7 to 12.2 hours, and no accumulation was observed with repeated dosing. PD evaluations confirmed inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs from patients by MGCD0103.
CONCLUSION
At doses evaluated, MGCD0103 appears tolerable and exhibits favorable PK and PD profiles with evidence of target inhibition in surrogate tissues.
Topics: Acetylation; Administration, Oral; Adult; Aged; Antineoplastic Agents; Benzamides; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Female; Histone Deacetylase Inhibitors; Histones; Humans; Leukocytes; Male; Middle Aged; Neoplasms; Patient Compliance; Pyrimidines
PubMed: 18421048
DOI: 10.1200/JCO.2007.14.5730