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Histone deacetylase (HDAC) inhibitors

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https://www.readbyqxmd.com/read/29328474/inhibition-of-mir%C3%A2-34a-prevents-endothelial-cell-apoptosis-by-directly-targeting-hdac1-in-the-setting-of-atherosclerosis
#1
Yangwei Li, Kang Zhang, Wei Mao
Despite recent medical advances, atherosclerosis is a global burden accounting for numerous mortalities and hospital admissions. MicroRNAs (miRNAs/miRs) regulate cardiovascular biology and disease, but the role of microRNA‑34a in atherosclerosis remains unclear. In the present study, it was demonstrated that miR‑34a was highly expressed in atherosclerotic lesions and oxidized low‑density lipoprotein (Ox‑LDL)‑treated human aortic endothelial cells (HAECs) (atherosclerotic cell model) using reverse transcription‑quantitative polymerase chain reaction...
January 9, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29327812/hyper-acetylation-contributes-to-the-sensitivity-of-chemo-resistant-prostate-cancer-cells-to-histone-deacetylase-inhibitor-trichostatin-a
#2
Qingqing Xu, Xiaofei Liu, Shiqin Zhu, Xuelei Hu, Huanmin Niu, Xiulei Zhang, Deyu Zhu, Effat Un Nesa, Keli Tian, Huiqing Yuan
Therapeutic agents are urgently needed for treating metastatic castration-refractory prostate cancer (mCRPC) that is unresponsive to androgen deprivation and chemotherapy. Our screening assays demonstrated that chemotherapy-resistant prostate cancer (PCa) cells are more sensitive to HDAC inhibitors than paired sensitive PCa cells, as demonstrated by cell proliferation and apoptosis in vitro and in vivo. Kinetic study revealed that TSA-induced apoptosis was significantly dependent on enhanced transcription and protein synthesis in an early stage, which subsequently caused ER stress and apoptosis...
January 12, 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29317660/microbiota-derived-short-chain-fatty-acids-promote-histone-crotonylation-in-the-colon-through-histone-deacetylases
#3
Rachel Fellows, Jérémy Denizot, Claudia Stellato, Alessandro Cuomo, Payal Jain, Elena Stoyanova, Szabina Balázsi, Zoltán Hajnády, Anke Liebert, Juri Kazakevych, Hector Blackburn, Renan Oliveira Corrêa, José Luís Fachi, Fabio Takeo Sato, Willian R Ribeiro, Caroline Marcantonio Ferreira, Hélène Perée, Mariangela Spagnuolo, Raphaël Mattiuz, Csaba Matolcsi, Joana Guedes, Jonathan Clark, Marc Veldhoen, Tiziana Bonaldi, Marco Aurélio Ramirez Vinolo, Patrick Varga-Weisz
The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation...
January 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29317217/crucial-role-of-ho-1-irf4-dependent-apoptosis-induced-by-panobinostat-and-lenalidomide-in-multiple-myeloma
#4
Sishi Tang, Dan Ma, Bingqing Cheng, Qing Fang, Xinyi Kuang, Kunling Yu, Weili Wang, Bo Hu, Jishi Wang
Inhibition of histone deacetylase (HDAC) is a promising therapeutic strategy for various hematologic cancers. Panobinostat has been approved for treating patients with multiple myeloma (MM) by the FDA. Since the mechanism for the resistance of panobinostat to MM remains elusive, we aimed to clarify this mechanism and the synergism of panobinostat with lenalidomide. The mRNA and protein of transcription factor IRF4 were overexpressed in CD138+ mononuclear cells from MM patients compared with in those from healthy donors...
January 6, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29317150/design-synthesis-and-evaluate-of-novel-dual-fgfr1-and-hdac-inhibitors-bearing-an-indazole-scaffold
#5
Jian Liu, Chengbo Qian, Yehua Zhu, Jianguo Cai, Yufang He, Jie Li, Tianlin Wang, Haohao Zhu, Zhi Li, Wei Li, Lihong Hu
Both histone deacetylase (HDAC) and fibroblast growth factor receptor (FGFR) are important targets for cancer therapy. Although combining dual HDAC pharmacophore with tyrosine kinase inhibitors (TKIs) had achieved a successful progress, dual HDAC/FGFR1 inhibitors haven't been reported yet. Herein, we designed a series of hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids scaffold with scaffold hopping and molecular hybridization strategies. Among them, compound 7j showed the most potent inhibitory activity against HDAC6 with IC50 of 34 nM and exhibited the great inhibitory activities against a human breast cancer cell line MCF-7 with IC50 of 9 μM in vitro...
December 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29316653/synergistic-association-of-valproate-and-resveratrol-reduces-brain-injury-in-ischemic-stroke
#6
Lara Faggi, Giuseppe Pignataro, Edoardo Parrella, Vanessa Porrini, Antonio Vinciguerra, Pasquale Cepparulo, Ornella Cuomo, Annamaria Lanzillotta, Mariana Mota, Marina Benarese, Paolo Tonin, Lucio Annunziato, PierFranco Spano, Marina Pizzi
Histone deacetylation, together with altered acetylation of NF-κB/RelA, encompassing the K310 residue acetylation, occur during brain ischemia. By restoring the normal acetylation condition, we previously reported that sub-threshold doses of resveratrol and entinostat (MS-275), respectively, an activator of the AMP-activated kinase (AMPK)-sirtuin 1 pathway and an inhibitor of class I histone deacetylases (HDACs), synergistically elicited neuroprotection in a mouse model of ischemic stroke. To improve the translational power of this approach, we investigated the efficacy of MS-275 replacement with valproate, the antiepileptic drug also reported to be a class I HDAC blocker...
January 6, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29313067/combinatorial-effects-of-histone-deacetylase-inhibitors-hdaci-vorinostat-and-entinostat-and-adaphostin-are-characterized-by-distinct-redox-alterations
#7
Nilsa Rivera-Del Valle, Tiewei Cheng, Mary E Irwin, Hayley Donnella, Melissa M Singh, Joya Chandra
PURPOSE: Amongst the epigenetically targeted therapies, targeting of the histone deacetylases (HDACs) has yielded numerous drugs for clinical use in hematological malignancies, but none as yet for acute lymphocytic leukemia (ALL). Single agent activity of HDAC inhibitors (HDACi) has been elusive in ALL, and has prompted study of combinatorial strategies. Because several HDACi raise levels of intracellular oxidative stress, we evaluated combinations of two structurally distinct HDACi with the redox active compound adaphostin in ALL...
January 8, 2018: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29312470/combined-inhibition-of-bet-proteins-and-class-i-hdacs-synergistically-induces-apoptosis-in-urothelial-carcinoma-cell-lines
#8
Alexander S Hölscher, Wolfgang A Schulz, Maria Pinkerneil, Günter Niegisch, Michèle J Hoffmann
Background: New efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types...
2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/29306016/pan-hdac-inhibition-by-panobinostat-mediates-chemosensitization-to-carboplatin-in-non-small-cell-lung-cancer-via-attenuation-of-egfr-signaling
#9
Lingzhi Wang, Nicholas Li-Xun Syn, Vinod Vijay Subhash, Yijia Any, Win Lwin Thuya, Esther Cheow, Liren Kong, Fenggang Yu, Praveen C Peethala, Andrea Li-Ann Wong, Hirpara J Laljibhai, Arunachalam Chinnathambi, Pei Shi Ong, Paul Chi-Lui Ho, Gautam Sethi, Wei Peng Yong, Boon Cher Goh
Accumulating evidence has implicated the aberrant regulation of histone deacetylases (HDACs) as a nexus for multiple cancer hallmarks and in mediating tumor adaptation and resistance to genotoxic chemotherapy, suggesting a rational pairing of HDAC inhibitors with DNA damaging chemotherapeutic agents in the treatment of human malignancies. Here we report that panobinostat (LBH589), a potent pan-HDAC inhibitor, effectively curbed the proliferation of non-small cell lung cancer (NSCLC) cell lines A549, Calu-1, H226, H460, H838 and SKMES-1 at IC50 concentrations between 4 and 31 nmol/L via pleiotropic mechanisms, including crosstalk with EGFR signal transduction cascades...
January 3, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29305109/scriptaid-inhibits-cell-survival-cell-cycle-and-promotes-apoptosis-in-multiple-myeloma-via-epigenetic-regulation-of-p21
#10
Ruosi Yao, Danyang Han, Xiaoyang Sun, Yu Xie, Qingyun Wu, Chunling Fu, Yao Yao, Hujun Li, Zhenyu Li, Kailin Xu
Multiple myeloma (MM) is an extremely serious plasma cell malignancy. Despite recent introduction of chemotherapies such as bortezomib and lenalidomide, it remains an incurable disease due to high rate of relapse and development of drug resistance. Epigenetic regulation is closely related with MM progression; nevertheless, the epigenetic modification mechanism of myeloma cell apoptosis has remained unclear. As a novel histone deacetylase inhibitor, Scriptaid's possible roles in MM progression have not been explored...
January 2, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29304284/-n-hydroxycarbonylbenylamino-quinolines-as-selective-histone-deacetylase-6-inhibitors-suppress-growth-of-multiple-myeloma-in-vitro-and-in-vivo
#11
Hsueh-Yun Lee, Kunal Nepali, Fang-I Huang, Chih-Yi Chang, Mei-Jung Lai, Yu-Hsuan Li, Hsiang-Ling Huang, Chia-Ron Yang, Jing-Ping Liou
A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4000-43000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60...
January 5, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29304031/the-histone-deacetylase-inhibitor-valproic-acid-exerts-a-synergistic-cytotoxicity-with-the-dna-damaging-drug-ellipticine-in-neuroblastoma-cells
#12
Tereza Cerna, Jan Hrabeta, Tomas Eckschlager, Eva Frei, Heinz H Schmeiser, Volker M Arlt, Marie Stiborová
Neuroblastoma (NBL) originates from undifferentiated cells of the sympathetic nervous system. Chemotherapy is judged to be suitable for successful treatment of this disease. Here, the influence of histone deacetylase (HDAC) inhibitor valproate (VPA) combined with DNA-damaging chemotherapeutic, ellipticine, on UKF-NB-4 and SH-SY5Y neuroblastoma cells was investigated. Treatment of these cells with ellipticine in combination with VPA led to the synergism of their anticancer efficacy. The effect is more pronounced in the UKF-NB-4 cell line, the line with N-myc amplification, than in SH-SY5Y cells...
January 5, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29302209/histone-deacetylase-inhibition-attenuates-hepatic-steatosis-in-rats-with-experimental-cushing-s-syndrome
#13
Mina Kim, Hae-Ahm Lee, Hyun-Min Cho, Seol-Hee Kang, Eunjo Lee, In Kyeom Kim
Cushing's syndrome (CS) is a collection of symptoms caused by prolonged exposure to excess cortisol. Chronically elevated glucocorticoid (GC) levels contribute to hepatic steatosis. We hypothesized that histone deacetylase inhibitors (HDACi) could attenuate hepatic steatosis through glucocorticoid receptor (GR) acetylation in experimental CS. To induce CS, we administered adrenocorticotropic hormone (ACTH; 40 ng/kg/day) to Sprague-Dawley rats by subcutaneous infusion with osmotic mini-pumps. We administered the HDACi, sodium valproate (VPA; 0...
January 2018: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/29302039/targeting-the-corest-complex-with-dual-histone-deacetylase-and-demethylase-inhibitors
#14
Jay H Kalin, Muzhou Wu, Andrea V Gomez, Yun Song, Jayanta Das, Dawn Hayward, Nkosi Adejola, Mingxuan Wu, Izabela Panova, Hye Jin Chung, Edward Kim, Holly J Roberts, Justin M Roberts, Polina Prusevich, Jeliazko R Jeliazkov, Shourya S Roy Burman, Louise Fairall, Charles Milano, Abdulkerim Eroglu, Charlotte M Proby, Albena T Dinkova-Kostova, Wayne W Hancock, Jeffrey J Gray, James E Bradner, Sergio Valente, Antonello Mai, Nicole M Anders, Michelle A Rudek, Yong Hu, Byungwoo Ryu, John W R Schwabe, Andrea Mattevi, Rhoda M Alani, Philip A Cole
Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes...
January 4, 2018: Nature Communications
https://www.readbyqxmd.com/read/29301535/inhibition-of-histone-deacetylase-activity-rescues-inflammatory-cystic-fibrosis-lung-disease-by-modulating-innate-and-adaptive-immune-responses
#15
Manish Bodas, Steven Mazur, Taehong Min, Neeraj Vij
BACKGROUND: Chronic lung disease resulting from dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) and NFκB-mediated neutrophilic-inflammation forms the basis of CF-related mortality. Here we aimed to evaluate if HDAC inhibition controls Pseudomonas-aeruginosa-lipopolysaccharide (Pa-LPS) induced airway inflammation and CF-lung disease. METHODS: For in vitro experiments, HEK293-cells were transfected with IL-8 or NFκB-firefly luciferase, and SV40-renilla- luciferase reporter constructs or ΔF508-CFTR-pCEP, followed by treatment with suberoylanilide hydroxamic acid (SAHA), Trichostatin-A (TSA) and/or TNFα...
January 4, 2018: Respiratory Research
https://www.readbyqxmd.com/read/29301348/modification-of-epigenetic-histone-acetylation-in-hepatocellular-carcinoma
#16
REVIEW
Kwei-Yan Liu, Li-Ting Wang, Shih-Hsien Hsu
Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor (AHR) is a unique cellular chemical sensor present in most organs, and its dysregulation has been demonstrated in multiple stages of tumor progression in humans and experimental models; however, the effects of the pathogenic mechanisms of AHR on epigenetic regulation remain unclear...
January 3, 2018: Cancers
https://www.readbyqxmd.com/read/29300993/the-existing-drug-vorinostat-as-a-new-lead-against-cryptosporidiosis-by-targeting-the-parasite-histone-deacetylases
#17
Fengguang Guo, Haili Zhang, Nina N McNair, Jan R Mead, Guan Zhu
Background: Cryptosporidiosis affects all human populations, but can be much more severe or life-threatening in children and individuals with weak or weakened immune systems. However, current options to treat cryptosporidiosis are limited. Methods: An in vitro phenotypic screening assay was employed to screen 1,200 existing drugs for their anti-cryptosporidial activity, and to determine the inhibitory kinetics of top hits. Selected top hits were further evaluated in mice...
January 2, 2018: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29299126/hdac-inhibition-as-a-treatment-concept-to-combat-temsirolimus-resistant-bladder-cancer-cells
#18
Eva Juengel, Ramin Najafi, Jochen Rutz, Sebastian Maxeiner, Jasmina Makarevic, Frederik Roos, Igor Tsaur, Axel Haferkamp, Roman A Blaheta
Introduction: Although the mechanistic target of rapamycin (mTOR) might be a promising molecular target to treat advanced bladder cancer, resistance develops under chronic exposure to an mTOR inhibitor (everolimus, temsirolimus). Based on earlier studies, we proposed that histone deacetylase (HDAC) blockade might circumvent resistance and investigated whether HDAC inhibition has an impact on growth of bladder cancer cells with acquired resistance towards temsirolimus. Results: The HDAC inhibitor valproic acid (VPA) significantly inhibited growth, proliferation and caused G0/G1 phase arrest in RT112res and UMUC-3res...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29298886/class-1-selective-histone-deacetylase-inhibitors-enhance-hiv-latency-reversal-while-preserving-the-activity-of-hdac-isoforms-necessary-for-maximal-hiv-gene-expression
#19
Thomas D Zaikos, Mark M Painter, Nadia T Sebastian, Valeri H Terry, Kathleen L Collins
Combinations of drugs that affect distinct mechanisms of HIV latency aim to induce robust latency reversal leading to cytopathicity and elimination of the persistent HIV reservoir. Thus far, attempts have focused on combinations of PKC agonists and pan-histone deacetylase inhibitors (HDIs) despite the knowledge that HIV gene expression is regulated by class 1 histone deacetylases. We hypothesized that class 1-selective HDIs would promote more robust HIV latency reversal in combination with a PKC agonist than pan-HDIs because they preserve the activity of pro-viral factors regulated by non-class 1 histone deacetylases...
January 3, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29290529/histone-deacetylase-inhibitor-hdaci-upregulates-activin-a-and-activates-the-smad-signaling-pathway-in-melanomas
#20
Jeeyong Lee, Jiwon Ko, Jae Youn Yi
BACKGROUND: Histone deacetylase (HDAC) is an enzyme that regulates gene expression, cell cycle arrest, apoptosis and modulation of various pathways. HDAC inhibitors (HDACis) can modulate these pathways by hyper-acetylating target proteins, thereby acting as cancer chemotherapeutic agents. OBJECTIVE: One of HDACis, suberoylanilide hydroxamic acid (SAHA), has been found to regulate the Smad signaling pathway, by an as yet unclear mechanism. This study therefore investigated the mechanism by which SAHA regulates Smad signaling in the melanoma cell line SK-Mel-5...
December 21, 2017: Journal of Dermatological Science
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