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HDAC inhibitor

Mikkel Staberg, Signe Regner Michaelsen, Rikke Darling Rasmussen, Mette Villingshøj, Hans Skovgaard Poulsen, Petra Hamerlik
PURPOSE: Glioblastoma (GBM) ranks among the deadliest solid cancers worldwide and its prognosis has remained dismal, despite the use of aggressive chemo-irradiation treatment regimens. Limited drug delivery into the brain parenchyma and frequent resistance to currently available therapies are problems that call for a prompt development of novel therapeutic strategies. While only displaying modest efficacies as mono-therapy in pre-clinical settings, histone deacetylase inhibitors (HDACi) have shown promising sensitizing effects to a number of cytotoxic agents...
October 20, 2016: Cellular Oncology (Dordrecht)
Gonzalo Lopez, Raphael E Pollock
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive disease with a dismal prognosis. The disease can occur sporadically or in patients with inherited neurofibromatosis (NF-1). MPNST is typically resistant to therapeutic intervention. Hence, the need for improved therapies is warranted. Several broad spectrum histone deacetylase (HDAC) inhibitors have a high affinity for class I HDAC isoforms. Inhibition of multiple HDAC isoforms often results in undesirable side effects, while inhibiting a single isoform could possibly improve the therapeutic window and limit toxicity...
2017: Methods in Molecular Biology
Mandy Beyer, Nicole Kiweler, Siavosh Mahboobi, Oliver H Krämer
Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues in their target proteins. This biochemical modification can have profound effects on the functions of these proteins and a dysregulation of HDAC activity contributes to severe diseases, including neoplastic transformation. In the following chapter, we present a strategy that allows to distinguish between the inhibition of the class I HDACs HDAC1, 2, and 3 and of the class IIb HDAC HDAC6. This method is based on Western blot and relies on the detection of hyperacetylated substrates of class I or class IIb HDACs in lysates from cells that were treated with histone deacetylase inhibitors (HDACi)...
2017: Methods in Molecular Biology
Sophia Pinz, Anne Rascle
Transcriptional activation by STAT5 is repressed by deacetylase inhibitors. Investigating the role of deacetylases (HDACs) in STAT5-mediated transcription implies the analysis of molecular events taking place at the chromatin level. We describe here two alternative methods of chromatin immunoprecipitation that allow the characterization of chromatin modifications ensuing STAT5 activation and its inhibition by deacetylase inhibitors, in particular changes in histone acetylation, in histone occupancy, and in the association/dissociation of transcription factors and other chromatin-associated factors...
2017: Methods in Molecular Biology
David Olagnier, Cindy Chiang, John Hiscott
The dynamics of chromatin structure contribute to the regulation of gene transcription and in part, the changes in chromatin structure associated with gene activation/repression are a function of the state of histone acetylation. Histone deacetylases (HDACs) deacetylate histone tails leading to a more compact structure of chromatin that in turn represses gene transcription. Given the rapid activation and/or repression of gene networks following microbial infection, the role of HDACs in the epigenetic regulation of genes involved in the innate and adaptive immune responses has become an area of extensive research...
2017: Methods in Molecular Biology
Dagmar Hildebrand, Katharina F Kubatzky
Flow cytometric techniques allow fast, sensitive, and multiparametric analyses at the single cell level. This makes it possible to distinguish subsets of cells within heterogeneous samples. Moreover, flow cytometry has become a frequently used method for the evaluation of therapeutic effects. Here, we describe the analysis of the phosphorylation status of signal transducer and activator of transcription-1 (STAT-1) in primary mouse cells after treatment with histone deacetylase inhibitors (HDACi) that are currently considered anticancer agents...
2017: Methods in Molecular Biology
Christina Susanne Mullins, Stephanie Bock, Mathias Krohn, Michael Linnebacher
Human tumor in vivo cancer models raised in immunodeficient mice, the so-called patient-derived xenografts, are increasingly in use in preclinical development and evaluation of novel drug candidates including HDAC inhibitors. Here, we describe the techniques needed to generate novel patient-derived xenografts. The focus lies on vitally frozen tumor biopsies as starting material. First, the preparative steps on the animals, followed by the engraftment procedure itself, the tumor growth surveillance, the explantation procedure, and finally the handling of obtained xenograft tissues are described step by step...
2017: Methods in Molecular Biology
Daniel Nettersheim, Sina Jostes, Hubert Schorle
Histone deacetylase inhibitor application is lethal to many cancer types. To screen for the therapeutic potential of HDIs it is necessary to analyze their ability to target and kill cancer cells in vivo. Here, we describe the xenografting of (germ cell) cancer cell lines into the flank of nude mice and the subsequent intravenous application of HDIs.
2017: Methods in Molecular Biology
Astrid Hagelkruys, Mirjam A Moser, Christian Seiser
Histone deacetylases (HDACs) play crucial roles during mammalian development and for cellular homeostasis. In addition, these enzymes are promising targets for small molecule inhibitors in the treatment of cancer and neurological diseases. Conditional HDAC knock-out mice are excellent tools for defining the functions of individual HDACs in vivo and for identifying the molecular targets of HDAC inhibitors in disease. Here, we describe the generation of tissue-specific HDAC knock-out mice and delineate a strategy for the generation of conditional HDAC knock-in mice...
2017: Methods in Molecular Biology
Annette Romanski, Gesine Bug
Histone deacetylase (HDAC) inhibitors are promising drugs. These agents lead to growth inhibition, cell cycle arrest, premature senescence, and apoptosis of malignant cells. Aim of our studies was to determine the efficacy of HDAC inhibitors on the clinically most relevant population of human leukemic progenitor cells in vitro. We here present stroma-free long-term cultures (LTC) of primary acute myeloid leukemia (AML) cells as a useful system for drug sensitivity testing in functional assays. AML-LTC are established by isolating mononuclear cells from peripheral blood samples of AML patients followed by selection of CD34(+) progenitor cells...
2017: Methods in Molecular Biology
Teodora Nikolova, Anja Göder, Ann Parplys, Kerstin Borgmann
DNA fiber spreading assay is an invaluable technique to visualize and follow the spatial and temporal progress of individual DNA replication forks. It provides information on the DNA replication progress and its regulation under normal conditions as well as on replication stress induced by environmental genotoxic agents or cancer drugs. The method relies on the detection of incorporated thymidine analogues during DNA synthesis in the S phase of the cell cycle by indirect immunofluorescence. Here, we describe the procedure established in our laboratories for sequential pulse labeling of human cells with 5-chloro-2'-deoxyuridine (CldU) and 5-iodo-2'-deoxyuridine (IdU), cell lysis, and DNA fiber spreading on slides and sequential immunodetection of the incorporated thymidine analogues by primary antibodies recognizing specifically CldU or IdU alone...
2017: Methods in Molecular Biology
Darren M Hutt, Daniela Martino Roth, Christelle Marchal, Marion Bouchecareilh
Gene expression is regulated in part through the reversible acetylation of histones, by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). HAT activity results in the addition of acetyl groups on the lysine residues of histone tails leading to decondensation of the chromatin, and increased gene transcription in general, whereas HDACs remove these acetyl groups, thus leading to an overall suppression of gene transcription. Recent evidence has elucidated that histones are not the only components of the proteome that are targeted by HATs and HDACs...
2017: Methods in Molecular Biology
Lisa Marx-Blümel, Christian Marx, Marie Kühne, Jürgen Sonnemann
The chromatin contains the genetic and the epigenetic information of a eukaryotic organism. Posttranslational modifications of histones, such as acetylation and methylation, regulate their structure and control gene expression. Histone acetyltransferases (HATs) acetylate lysine residues in histones while histone deacetylases (HDACs) remove this modification. HDAC inhibitors (HDACi) can alter gene expression patterns and induce cytotoxicity in cancer cells. Here we provide an overview of methods to determine the cytotoxic effects of HDACi treatment...
2017: Methods in Molecular Biology
Fabian Treude, Tobias Gladbach, Jacqueline Plaster, Jörg Hartkamp
Aberrant histone deacetylase (HDAC) activity often correlates with neoplastic transformation and inhibition of HDACs by small molecules has emerged as a promising strategy to treat hematological malignancies in particular. Treatment with HDAC inhibitors (HDACis) often prompts tumor cells to undergo apoptosis, thereby causing a caspase-dependent cleavage of target proteins. An unexpectedly large number of proteins are in vivo caspase substrates and defining caspase-mediated substrate specificity is a major challenge...
2017: Methods in Molecular Biology
Anja Göder, Nisintha Mahendrarajah, Oliver H Krämer
Autophagy is a lysosome-dependent, intracellular pathway for the recycling of cellular components. It plays a pivotal role in both cancer development and the response to chemotherapy. Here we describe how autophagy can be monitored in living cells by flow cytometry using the cationic amphiphilic tracer dye Cyto-ID(®) Green. The detection of autophagy induction in the human leukemia cell line K562 after the treatment with the HDAC class I inhibitor MS-275 serves as an example for this approach.
2017: Methods in Molecular Biology
Carmine Carbone, Elena Di Gennaro, Geny Piro, Maria Rita Milone, Biagio Pucci, Michele Caraglia, Alfredo Budillon
Vorinostat demonstrated preclinical and clinical efficacy in human cancers and is the first histone deacetylase inhibitor (HDACi) approved for cancer treatment. Tissue transglutaminase (TG2) is a multifunctional enzyme that catalyzes a Ca(2+) dependent transamidating reaction resulting in covalent cross-links between proteins. TG2 acts also as G-protein in trans-membrane signaling and as a cell surface adhesion mediator. TG2 up-regulation has been demonstrated in several cancers and its expression levels correlate with resistance to chemotherapy and metastatic potential...
October 19, 2016: Amino Acids
Arianna Bottoni, Lara Rizzotto, Tzung-Huei Lai, Chaomei Liu, Lisa L Smith, Rose Mantel, Sean Reiff, Dalia El-Gamal, Karilyn Larkin, Amy J Johnson, Rosa Lapalombella, Amy Lehman, William Plunkett, John C Byrd, James S Blachly, Jennifer A Woyach, Deepa Sampath
BTK is a critical mediator of survival in B cell neoplasms. While BTK inhibitors have transformed therapy in CLL, high genetic risk patients are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of miRNAs that target BTK in primary CLL cells and show that the HDAC repressor complex is recruited to these miRNA promoters to silence their expression...
October 17, 2016: Blood
Claire E Weston, Andreas Kraemer, Felix Colin, Özkan Yildiz, Matthias G J Baud, Franz-Josef Meyer-Almes, Matthew J Fuchter
Photopharmacological agents exhibit light-dependent biological activity and may have potential in the development of new antimicrobial agents/modalities. Amidohydrolase enzymes homologous to the well known human histone deacetylases (HDACs) are present in bacteria, including resistant organisms responsible for a significant number of hospital acquired infections and deaths. We report photopharmacological inhibitors of these enzymes, using two classes of photoswitch embedded in the inhibitor pharmacophore: azobenzenes and arylazopyrazoles...
October 18, 2016: ACS Infectious Diseases
Jesse McClure, Cheng Zhang, Elizabeth Inks, Yuri K Peterson, Jiaying Li, C James Chou
One of the biggest hurdles yet to be overcome for the continued improvement of Histone Deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The N-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans; compounds containing this motif require much higher dosing in clinic to achieve therapeutic concentrations. With the goal of developing a second generation of HDAC inhibitors, lacking this hydroxamate, we designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif...
October 18, 2016: Journal of Medicinal Chemistry
InKyeom Kim
Histone deacetylases (HDACs) act as co-repressors in gene transcription by erasing the acetylation of histones, resulting in epigenetic gene silencing. Recent studies revealed that HDAC inhibitors attenuated blood pressure of several hypertensive animal models such as spontaneously hypertensive rats, hyperaldosteronism rats, angiotensin II-induced hypertensive rats and pulmonary hypertensive rats. Unexpectedly, microarray studies uncovered that administration of HDAC inhibitors decreased expression of some genes for example extracellular matrix proteins, oxidative stress-related proteins, cytokines, chemokines and ion transporters, mostly targets of corticoid receptors...
September 2016: Journal of Hypertension
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