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Histone deacetylase inhibitor

Dimitry A Chistiakov, Veronika A Myasoedova, Alexander N Orekhov, Yuri V Bobryshev
Epigenetic mechanisms, which are involved in the regulation of gene expression, are tightly controlled. Loss of a proper epigenetic control can lead to global epigenetic alterations frequently observed in various diseases including cancer. Aberrant epigenetic changes induced in malignant cells lead to emergence of neoplastic properties, which inhibit cell differentiation and strict cell cycle control but greatly enhance stemness-related features. However, abnormal epigenetic patterns can be reversed by action of epigenetically active agents...
October 21, 2016: Current Pharmaceutical Design
Heidy Martínez-Pacheco, Guillermo Ramírez-Galicia, Midalia Vergara-Arias, Jürg Gertsch, Jonathan Manuel Fragoso-Vázquez, David Méndez-Luna, A L Abujamra, Cabrera-Pérez Laura Cristina, Rosales-Hernández Martha Cecilia, I Mendoza-Lujambio, José Correa-Basurto
Histone deacetylase 8 (HDAC8) is a plausible target for the development of novel anticancer drugs using a metal-chelating group and hydrophobic moieties as pharmacophores. It is known that valproic acid (administered as its salt, sodium valproate; VPANa+) is an HDAC8 inhibitor characterized by its hydrophobic chains. Nevertheless, VPA is hepatotoxic and VPA analogues might be explored for less hepatotoxic antiproliferative compounds. In this work, docking and QSAR studies of 500 aryl-VPA derivatives as possible HDAC8 inhibitors were performed in order to explore and select potential anti-proliferative compounds...
October 19, 2016: Anti-cancer Agents in Medicinal Chemistry
Oscar J Ingham, Ronald M Paranal, William B Smith, Randolph A Escobar, Han Yueh, Tracy Snyder, John A Porco, James E Bradner, Aaron B Beeler
A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8.
October 13, 2016: ACS Medicinal Chemistry Letters
Ruirui Han, Qianqian Sun, Jianbo Wu, Pengyuan Zheng, Guoqiang Zhao
BACKGROUND: As the end product of the bacterial fermentation of dietary fiber in the colonic lumen, sodium butyrate (NaBt) has been reported to exert antitumor effects on colorectal cancer (CRC). In addition to functioning as a histone deacetylase (HDAC) inhibitor, NaBt also regulates the expression of microRNAs (miRNAs) to inhibit CRC cell proliferation. Yet, the mechanisms involved are not completely understood. Here we investigate whether NaBt regulates miR-203 to inhibit CRC growth and explore the promising target gene of miR-203 in CRC cells...
October 24, 2016: Cellular Physiology and Biochemistry
Erika Heninger, Timothy E G Krueger, Stephanie M Thiede, Jamie M Sperger, Brianna L Byers, Madison R Kircher, David Kosoff, Bing Yang, David F Jarrard, Douglas G McNeel, Joshua M Lang
Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2'-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589...
October 17, 2016: Oncotarget
Gianluigi Franci, Federica Sarno, Angela Nebbioso, Lucia Altucci
Epigenetic modifications are functionally involved in gene expression regulation. In particular, histone posttranslational modifications play a crucial role in functional chromatin organization. Several drugs able to inhibit or stimulate some families of proteins involved in epigenetic histone regulation have been found, a number of which are FDA-approved for the treatment of cutaneous T-cell lymphoma or are in phase I/II/III clinical trials for solid tumors. Although some protein families, such as histone deacetylases and their inhibitors, are well characterized, our understanding of histone lysine demethylases is still incomplete...
October 21, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Andrew Kl Goey, Tristan M Sissung, Cody J Peer, William D Figg
The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment...
October 21, 2016: Pharmacogenomics
E Faghihloo, Y Araei, M Mohammadi, H Mirzaei, H R Mohammadi, T Mokhtari-Azad
Gastric cancer is among the leading causes of cancer-related death, and the symptoms are commonly characterized in advanced stages. Histone acetylation is among the most important epigenetic alterations occurring during cancer development. In addition, reduced E-cadherin expression is a major contributor in the process of tumor cell invasion and metastasis. Oxamflatin is a histone deacetylase inhibitor that has been suggested as a promising anti-tumor agent; yet its effect on the viability and invasion of gastric tumor cells is unclear...
October 21, 2016: Cancer Gene Therapy
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)
Maria Graziella Catalano, Mariateresa Pugliese, Marco Gallo, Enrico Brignardello, Paola Milla, Fabio Orlandi, Paolo Piero Limone, Emanuela Arvat, Giuseppe Boccuzzi, Alessandro Piovesan
Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy...
2016: International Journal of Endocrinology
Kishore Polireddy, Ruochen Dong, Peter R McDonald, Tao Wang, Brendan Luke, Ping Chen, Melinda Broward, Anuradha Roy, Qi Chen
BACKGROUND: Pancreatic cancer has an enrichment of stem-like cancer cells (CSCs) that contribute to chemoresistant tumors prone to metastasis and recurrence. Drug screening assays based on cytotoxicity cannot identify specific CSC inhibitors, because CSCs comprise only a small portion of cancer cell population, and it is difficult to propagate stable CSC populations in vitro for high-throughput screening (HTS) assays. Based on the important role of cancer cell epithelial-to-mesenchymal transition (EMT) in promoting CSCs, we hypothesized that inhibition of EMT can be a useful strategy for inhibiting CSCs, and therefore a feasible approach for HTS can be built for identification of CSC inhibitors, based on assays detecting EMT inhibition...
2016: PloS One
Siavosh Mahboobi, Bernadette Pilsl, Andreas Sellmer
Chimeric compounds combine the structural features of inhibitors of histone deacetylases (HDACi) and tyrosine kinase inhibitors (TKi), and therefore unite the effects of a dual-targeting strategy in one compound. Here, we describe the generation of such hybrid molecules. Small molecules, known as TKi, are combined with a Zn(2+) chelating motive, preferentially a hydroxamic acid, in addition. The resulting small molecules also can inhibit histone deacetylases, which are dependent on the catalytically active Zn(2+)...
2017: Methods in Molecular Biology
Vilwanathan Ravikumar, Renu Sankar
Nanotechnology is a comparatively new branch of science that includes harnessing the unique properties of particles that are nanometers in scale. Nanoparticles can be tailored in a precise fashion where their size, composition, and surface chemistry can be carefully controlled. The nanoprecipitation is a simple, powerful, and low-energy requiring technique, commonly used for the preparation of defined nanoparticles. Histone deacetylase inhibitor Vorinostat-loaded Poly D, L-lactide-co-glycolide (PLGA) polymeric nanoparticles were prepared by the nanoprecipitation technique...
2017: Methods in Molecular Biology
Dorle Hennig, Diana Imhof
Incorporation of drugs into particles can improve their therapeutic effectiveness. Solubility, half-life time, targeting, and the release of the drug can be modified by the encapsulation into a particle. Histone deacetylase inhibitors have a great potential to be used as therapeutics for many different diseases. In this chapter, we describe the inclusion of the low molar mass HDACi Ex527 into polymer-based particles and liposomes.
2017: Methods in Molecular Biology
Katrin Noack, Oliver H Krämer
The differentiation of hematopoietic stem cells into mature blood cells is a highly ordered process and dysregulation of this process can lead to leukemogenesis. Agents that are used to cure acute promyelocytic leukemia (APL) can induce differentiation and/or apoptosis. Here, we describe how effects of all-trans retinoic acid (ATRA) and histone deacetylase inhibitors (HDACi) on APL cell differentiation can be evaluated by immunoblotting and by flow cytometry. We show how the levels of differentiation-associated transcription factors of the CCAAT enhancer binding protein (C/EBP) family can be determined by Western blot and we explain how the cell surface expression of the leukocyte surface antigen CD11b can be measured by flow cytometry...
2017: Methods in Molecular Biology
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
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