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Mocetinostat

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https://www.readbyqxmd.com/read/27863907/evidence-of-epigenetic-tags-in-cardiac-fibrosis
#1
REVIEW
Vincenzo Grimaldi, Maria Rosaria De Pascale, Alberto Zullo, Andrea Soricelli, Teresa Infante, Francesco Paolo Mancini, Claudio Napoli
In cardiac fibrosis, following an injury or a stress, non-functional fibrotic tissue substitutes normal myocardium, thus leading to progressive heart failure. Activated fibroblasts are principal determinants of cardiac fibrosis by producing excessive fibrotic extracellular matrix and causing hypertrophy of cardiomyocytes. Epigenetic changes, such as DNA methylation, histone modifications, and miRNAs have been involved in these mechanisms. Therefore, there is a strong interest in reverting such epigenetic transformations in order to arrest myocardial fibrotic degeneration...
November 15, 2016: Journal of Cardiology
https://www.readbyqxmd.com/read/27666412/colorectal-cancer-cell-derived-microrna200-modulates-the-resistance-of-adjacent-blood-endothelial-barriers-in%C3%A2-vitro
#2
Silvio Holzner, Daniel Senfter, Serena Stadler, Anna Staribacher, Chi Huu Nguyen, Anna Gaggl, Silvana Geleff, Nicole Huttary, Sigurd Krieger, Walter Jäger, Helmut Dolznig, Robert M Mader, Georg Krupitza
Since cancer cells, when grown as spheroids, display drug sensitivity and radiation resistance patterns such as seen in vivo we recently established a three‑dimensional (3D) in vitro model recapitulating colorectal cancer (CRC)-triggered lymphatic endothelial cell (LEC)‑barrier breaching to study mechanisms of intra‑/extravasation. CRC metastasizes not only through lymphatics but also through blood vessels and here we extend the 3D model to the interaction of blood endothelial cells (BECs) with naïve and 5‑fluorouracil (5‑FU)‑resistant CRC CCL227 cells...
November 2016: Oncology Reports
https://www.readbyqxmd.com/read/27551531/an-epithelial-marker-promoter-induction-screen-identifies-histone-deacetylase-inhibitors-to-restore-epithelial-differentiation-and-abolishes-anchorage-independence-growth-in-cancers
#3
H M Tang, K T Kuay, P F Koh, M Asad, T Z Tan, V Y Chung, S C Lee, J P Thiery, Ry-J Huang
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...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/27551526/class-i-hdac-inhibitor-mocetinostat-induces-apoptosis-by-activation-of-mir-31-expression-and-suppression-of-e2f6
#4
Q Zhang, M Sun, S Zhou, B Guo
The class I selective inhibitor of the histone deacetylases, mocetinostat, has promising antitumor activities in both preclinical studies and the clinical trials. To understand how mocetinostat induces apoptosis, we examined the effects of mocetinostat on miR-31, a proapoptotic microRNA that was previously found to be epigenetically silenced in prostate cancer. We found that miR-31 was significantly upregulated by mocetinostat in prostate cancer cells. Antiapoptotic protein E2F6, the target of miR-31, was decreased by mocetinostat treatment...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/27499916/hr23b-expression-is-a-potential-predictive-biomarker-for-hdac-inhibitor-treatment-in-mesenchymal-tumours-and-is-associated-with-response-to-vorinostat
#5
Michaela Angelika Ihle, Sabine Merkelbach-Bruse, Wolfgang Hartmann, Sebastian Bauer, Nancy Ratner, Hiroshi Sonobe, Jun Nishio, Olle Larsson, Pierre Åman, Florence Pedeutour, Takahiro Taguchi, Eva Wardelmann, Reinhard Buettner, Hans-Ulrich Schildhaus
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...
April 2016: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/27278287/histone-deacetyltransferase-inhibitors-trichostatin-a-and-mocetinostat-differentially-regulate-mmp9-il-18-and-reck-expression-and-attenuate-angiotensin-ii-induced-cardiac-fibroblast-migration-and-proliferation
#6
Naveen K Somanna, Anthony J Valente, Maike Krenz, Kerry S McDonald, Yusuke Higashi, Makoto Noda, Bysani Chandrasekar
Histone acetylation/deacetylation plays a key role in the epigenetic regulation of multiple pro-fibrotic genes. Here we investigated the effects of histone deacetyltransferase (HDAC) inhibition on angiotensin (Ang)-II-induced pro-fibrotic changes in adult mouse cardiac fibroblasts (CF). CF express class I HDACs 1 and 2, and Ang-II induces their activation. Notably, silencing HDAC1 or HDAC2 attenuated Ang-II induced CF proliferation and migration. Under basal conditions, HDAC1 dimerizes with HDAC2 in CF and Ang-II reversed this interaction...
June 9, 2016: Hypertension Research: Official Journal of the Japanese Society of Hypertension
https://www.readbyqxmd.com/read/27249803/profile-of-class-i-histone-deacetylases-hdac-by-human-dendritic-cells-after-alcohol-consumption-and-in-vitro-alcohol-treatment-and-their-implication-in-oxidative-stress-role-of-hdac-inhibitors-trichostatin-a-and-mocetinostat
#7
Marisela Agudelo, Gloria Figueroa, Tiyash Parira, Adriana Yndart, Karla Muñoz, Venkata Atluri, Thangavel Samikkannu, Madhavan P Nair
Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of histone deacetylases (HDACs) on alcohol-induced oxidative stress of human primary monocyte-derived dendritic cells (MDDCs) has not been elucidated. In the current study, we took a novel approach combining ex vivo, in vitro and in silico analyses to elucidate the mechanisms of alcohol-induced oxidative stress and role of HDACs in the periphery. ex vivo and in vitro analyses of alcohol-modulation of class I HDACs and activity by MDDCs from self-reported alcohol users and non-alcohol users was performed...
2016: PloS One
https://www.readbyqxmd.com/read/26721445/hdac-inhibitors-induce-global-changes-in-histone-lysine-and-arginine-methylation-and-alter-expression-of-lysine-demethylases
#8
Ryan Lillico, Marina Gomez Sobral, Nicholas Stesco, Ted M Lakowski
Histone deacetylase (HDAC) inhibitors are cancer treatments that inhibit the removal of the epigenetic modification acetyllysine on histones, resulting in altered gene expression. Such changes in expression may influence other histone epigenetic modifications. We describe a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify lysine acetylation and methylation and arginine methylation on histones extracted from cultured cells treated with HDAC inhibitors. The HDAC inhibitors vorinostat, mocetinostat and entinostat induced 400-600% hyperacetylation in HEK 293 and K562 cells...
February 5, 2016: Journal of Proteomics
https://www.readbyqxmd.com/read/26464683/metabolic-changes-in-rats-after-intragastric-administration-of-mgcd0103-mocetinostat-a-hdac-class-i-inhibitor
#9
Qingwei Zhang, Haiya Wu, Congcong Wen, Fa Sun, Xuezhi Yang, Lufeng Hu
MGCD0103, an isotype-selective HDACi, has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In this study, we developed a serum metabolomic method based on gas chromatography-mass spectrometry (GC-MS) to evaluate the effect of intragastric administration of MGCD0103 on rats. The MGCD0103 group rats were given 20, 40, 80 mg/kg of MGCD0103 by intragastric administration each day for 7 days. Pattern recognition analysis, including both principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) revealed that intragastric administration of MGCD0103 induced metabolic perturbations...
2015: International Journal of Clinical and Experimental Pathology
https://www.readbyqxmd.com/read/26378038/induction-of-usp17-by-combining-bet-and-hdac-inhibitors-in-breast-cancer-cells
#10
Gabor Borbely, Lars-Arne Haldosen, Karin Dahlman-Wright, Chunyan Zhao
Members of the bromodomain and extra-C terminal (BET) domain protein family and the histone deacetylase (HDAC) enzyme family regulate the expression of important oncogenes and tumor suppressor genes. Here we show that the BET inhibitor JQ1 inhibits proliferation and induces apoptosis of both triple negative and estrogen receptor positive breast cancer cells. Consistent with the critical role of histone acetylation in the regulation of gene expression, treatment with JQ1 or the HDAC inhibitor mocetinostat was associated with global changes in gene expression resulting in suppression of genes involved in cell-cycle regulation...
October 20, 2015: Oncotarget
https://www.readbyqxmd.com/read/26287310/potent-and-selective-inhibitors-of-histone-deacetylase-3-containing-chiral-oxazoline-capping-groups-and-a-n-2-aminophenyl-benzamide-binding-unit
#11
Charles M Marson, Christopher J Matthews, Stephen J Atkinson, Nermina Lamadema, N Shaun B Thomas
A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k...
September 10, 2015: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26240433/transplantation-of-epigenetically-modified-adult-cardiac-c-kit-cells-retards-remodeling-and-improves-cardiac-function-in-ischemic-heart-failure-model
#12
Liudmila Zakharova, Hikmet Nural-Guvener, Lorraine Feehery, Snjezana Popovic-Sljukic, Mohamed A Gaballa
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...
September 2015: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/26091518/epigenetic-activity-of-peroxisome-proliferator-activated-receptor-gamma-agonists-increases-the-anticancer-effect-of-histone-deacetylase-inhibitors-on-multiple-myeloma-cells
#13
Nassera Aouali, Angeliki Broukou, Manon Bosseler, Olivier Keunen, Vincent Schlesser, Bassam Janji, Valerie Palissot, Philippe Stordeur, Guy Berchem
Epigenetic modifications play a major role in the development of multiple myeloma. We have previously reported that the PPARγ agonist pioglitazone (PIO) enhances, in-vitro, the cytotoxic effect of the Histone deacetylase inhibitor (HDACi), valproic acid (VPA), on multiple myeloma cells. Here, we described the development of a new multiple myeloma mouse model using MOLP8 cells, in order to evaluate the effect of VPA/PIO combination on the progression of myeloma cells, by analyzing the proliferation of bone marrow plasma cells...
2015: PloS One
https://www.readbyqxmd.com/read/25997003/anti-fibrotic-effects-of-class-i-hdac-inhibitor-mocetinostat-is-associated-with-il-6-stat3-signaling-in-ischemic-heart-failure
#14
Hikmet Nural-Guvener, Liudmila Zakharova, Lorraine Feehery, Snjezana Sljukic, Mohamed Gaballa
BACKGROUND: Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking chromatin remodeling events with observed anti-fibrotic effects are unknown. Here, we investigated the molecular players involved in anti-fibrotic effects of HDAC inhibition in congestive heart failure (CHF) myocardium and cardiac fibroblasts in vivo. METHODS AND RESULTS: MI was created by coronary artery occlusion...
2015: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/25872941/zeb1-associated-drug-resistance-in-cancer-cells-is-reversed-by-the-class-i-hdac-inhibitor-mocetinostat
#15
Simone Meidhof, Simone Brabletz, Waltraut Lehmann, Bogdan-Tiberius Preca, Kerstin Mock, Manuel Ruh, Julia Schüler, Maria Berthold, Anika Weber, Ulrike Burk, Michael Lübbert, Martin Puhr, Zoran Culig, Ulrich Wellner, Tobias Keck, Peter Bronsert, Simon Küsters, Ulrich T Hopt, Marc P Stemmler, Thomas Brabletz
Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial-mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT-activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance...
April 14, 2015: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/25782916/hdac-inhibitors-as-novel-anti-cancer-therapeutics
#16
REVIEW
Cristabelle De Souza, Biswa Prasun Chatterji
Malignant growth of cells is a condition characterized by unchecked cellular proliferation, genetic instability and epigenetic dysregulation. Up-regulated HDAC (Histone Deacetylase) enzyme activity is associated with a closed chromatin assembly and subsequent gene repression, forming a characteristic feature of malignantly transformed cells. Novel therapeutics are now targeting the zinc containing HDAC enzymes for treating various types of cancers. Recently, a spate of drugs acting via HDAC inhibition have been undergoing clinical trials and several patents present exciting molecules like PCI-24781 (Abexinostat), ITF- 2357 (Givinostat); MS-275 (Entinostat), MGCD 0103 (Mocetinostat), LBH-589 (Panobinostat), FK228 (Romidepsin), PXD-101 (Belinostat) and Valproic Acid to be used as alternatives or adjuvants to traditional chemotherapeutics...
2015: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/25341045/hdac1-and-klf4-interplay-critically-regulates-human-myeloid-leukemia-cell-proliferation
#17
Y Huang, J Chen, C Lu, J Han, G Wang, C Song, S Zhu, C Wang, G Li, J Kang, J Wang
Acute myeloid leukemia (AML) is recognized as a complex disease of hematopoietic stem cell disorders, but its pathogenesis mechanisms, diagnosis, and treatment remain unclear. General histone deacetylase (HDAC) inhibitors have been used in blood cancers including AML, but the lack of gene specificity greatly limits their anti-cancer effects and clinical applications. Here, we found that HDAC1 expression was negatively correlated with that of Krüppel-like factor 4 (Klf4) and that AML patients with lower HDAC1 level had better prognosis...
2014: Cell Death & Disease
https://www.readbyqxmd.com/read/25024745/hdac-class-i-inhibitor-mocetinostat-reverses-cardiac-fibrosis-in-heart-failure-and-diminishes-cd90-cardiac-myofibroblast-activation
#18
Hikmet F Nural-Guvener, Luidmila Zakharova, James Nimlos, Snjezana Popovic, Diego Mastroeni, Mohamed A Gaballa
BACKGROUND: Interstitial fibrosis and fibrotic scar formation contribute to cardiac remodeling and loss of cardiac function in myocardial infarction (MI) and heart failure. Recent studies showed that histone deacetylase (HDAC) inhibitors retard fibrosis formation in acute MI settings. However, it is unknown whether HDAC inhibition can reverse cardiac fibrosis in ischemic heart failure. In addition, specific HDAC isoforms involved in cardiac fibrosis and myofibroblast activation are not well defined...
2014: Fibrogenesis & Tissue Repair
https://www.readbyqxmd.com/read/24833798/transcriptional-regulation-of-endothelial-arginase-2-by-histone-deacetylase-2
#19
Deepesh Pandey, Gautam Sikka, Yehudit Bergman, Jae Hyung Kim, Sungwoo Ryoo, Lewis Romer, Dan Berkowitz
OBJECTIVE: Arginase 2 (Arg2) is a critical target in atherosclerosis because it controls endothelial nitric oxide, proliferation, fibrosis, and inflammation. Regulators of Arg2 transcription in the endothelium have not been characterized. The goal of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial Arg2 transcription and endothelial function. APPROACH AND RESULTS: The HDAC inhibitor trichostatin A increased levels of Arg2 mRNA, protein, and activity in both human aortic endothelial cells and mouse aortic rings...
July 2014: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/24749769/an-update-on-emerging-drugs-for-hodgkin-lymphoma
#20
REVIEW
Bastian von Tresckow, Volker Diehl
INTRODUCTION: Most patients with Hodgkin lymphoma (HL) are cured with modern combined modality first-line treatments. Even ~ 50% of patients with relapsed/refractory HL can be cured with high-dose chemotherapy (HDCT) and autologous stem cell transplantation. However, chemotherapy and radiotherapy cause significant acute and long-term side effects and patients relapsing after HDCT have a dismal prognosis. New drugs are therefore needed to reduce the toxicity of first-line treatments and to increase the efficacy of relapse treatments...
June 2014: Expert Opinion on Emerging Drugs
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