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Histone deacetylase (HDAC) inhibitors

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https://www.readbyqxmd.com/read/28326839/entinostat-a-promising-treatment-option-for-patients-with-advanced-breast-cancer
#1
Roisin M Connolly, Michelle A Rudek, Richard Piekarz
Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does not currently have regulatory approval for clinical use; however promising preclinical and clinical data exist in hormone-resistant breast cancer...
March 9, 2017: Future Oncology
https://www.readbyqxmd.com/read/28326191/global-histone-modification-fingerprinting-in-human-cells-using-epigenetic-reverse-phase-protein-array
#2
Marina Partolina, Hazel C Thoms, Kenneth G MacLeod, Giovanny Rodriguez-Blanco, Matthew N Clarke, Anuroop V Venkatasubramani, Rima Beesoo, Vladimir Larionov, Vidushi S Neergheen-Bhujun, Bryan Serrels, Hiroshi Kimura, Neil O Carragher, Alexander Kagansky
The balance between acetylation and deacetylation of histone proteins plays a critical role in the regulation of genomic functions. Aberrations in global levels of histone modifications are linked to carcinogenesis and are currently the focus of intense scrutiny and translational research investments to develop new therapies, which can modify complex disease pathophysiology through epigenetic control. However, despite significant progress in our understanding of the molecular mechanisms of epigenetic machinery in various genomic contexts and cell types, the links between epigenetic modifications and cellular phenotypes are far from being clear...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28321257/class-specific-histone-deacetylase-inhibitors-promote-11-beta-hydroxysteroid-dehydrogenase-type-2-expression-in-jeg-3-cells
#3
Katie L Togher, Louise C Kenny, Gerard W O'Keeffe
Exposure to maternal cortisol plays a crucial role in fetal organogenesis. However, fetal overexposure to cortisol has been linked to a range of short- and long-term adverse outcomes. Normally, this is prevented by the expression of an enzyme in the placenta called 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2) which converts active cortisol to its inactive metabolite cortisone. Placental 11β-HSD2 is known to be reduced in a number of adverse pregnancy complications, possibly through an epigenetic mechanism...
2017: International Journal of Cell Biology
https://www.readbyqxmd.com/read/28317157/design-and-synthesis-of-novel-anti-plasmodial-histone-deacetylase-inhibitors-containing-an-alkoxyamide-connecting-unit
#4
Leandro A Alves Avelar, Jana Held, Jessica A Engel, Parichat Sureechatchaiyan, Finn K Hansen, Alexandra Hamacher, Matthias U Kassack, Benjamin Mordmüller, Katherine T Andrews, Thomas Kurz
Despite recent declines in mortality, malaria remains an important global health problem. New therapies are needed, including new drugs with novel modes of action compared to existing agents. Among new potential therapeutic targets for malaria, inhibition of parasitic histone deacetylases (HDACs) is a promising approach. Homology modeling of PfHDAC1, a known target of some anti-plasmodial HDAC inhibitors, revealed a unique threonine residue at the rim of the active site in close proximity to the location of the cap group of vorinostat-type HDAC inhibitors...
March 20, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28315487/xpln-is-modulated-by-hdac-inhibitors-and-negatively-regulates-sparc-expression-by-targeting-mtorc2-in-human-lung-fibroblasts
#5
Koichiro Kamio, Arata Azuma, Jiro Usuki, Kuniko Matsuda, Minoru Inomata, Nobuhiko Nishijima, Shioto Itakura, Hiroki Hayashi, Takeru Kashiwada, Nariaki Kokuho, Kenichiro Atsumi, Tomoyoshi Yamaguchi, Kazue Fujita, Yoshinobu Saito, Shinji Abe, Kaoru Kubota, Akihiko Gemma
Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extracellular matrix, whose expression is regulated by transforming growth factor (TGF)-β1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown...
March 14, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28315153/effects-of-histone-deacetylase-inhibitory-prodrugs-on-epigenetic-changes-and-dna-damage-response-in-tumor-and-heart-of-glioblastoma-xenograft
#6
Nataly Tarasenko, Abraham Nudelman, Gabriela Rozic, Suzanne M Cutts, Ada Rephaeli
The histone deacetylase (HDAC) inhibitory prodrugs of butyric (AN7) and valproic (AN446) acids, which release the active acids upon metabolic degradation, were studied examining their differential effects on the viability, HDAC inhibitory activity and the DNA damage response (DDR), in glioblastoma cell and normal human astrocytes (NHAs). In xenografts of glioblastoma, AN7 or AN446 given or the combination of each of them with Dox augmented the anticancer activity of Dox and protected the heart from its toxicity...
March 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28306192/histone-deacetylase-activity-mediates-acquired-resistance-towards-structurally-diverse-hsp90-inhibitors
#7
Ryan C Chai, Jessica L Vieusseux, Benjamin J Lang, Chau H Nguyen, Michelle M Kouspou, Kara L Britt, John T Price
Heat Shock Protein 90 (HSP90) regulates multiple signaling pathways critical for tumor growth. As such, HSP90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may the presence of de novo or acquired resistance within the tumors. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the HSP90 inhibitor 17-AAG...
March 17, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28288848/bcl11b-mediated-epigenetic-repression-is-a-crucial-target-for-histone-deacetylase-inhibitors-in-cutaneous-t-cell-lymphoma
#8
Wenjing Fu, Shengguo Yi, Lei Qiu, Jingru Sun, Ping Tu, Yang Wang
The treatment options for advanced cutaneous T-cell lymphoma (CTCL) are limited due to its unclear pathogenesis. HDAC inhibitors (HDACi) are recently developed therapeutics approved for refractory CTCL. However, the response rate is relatively low and unpredictable. Previously, we discovered that BCL11B, a key T-cell development regulator, was aberrantly overexpressed in mycosis fungoides (MF), the most common CTCL, as compared with benign inflammatory skin. In the current study, we identified positive correlation between BCL11B expression and the sensitivity to HDACi in CTCL lines...
March 10, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28283560/hdac7-ubiquitination-by-the-e3-ligase-cbx4-is-involved-in-contextual-fear-conditioning-memory-formation
#9
Xu Jing, Wen-Hai Sui, Shuai Wang, Xu-Feng Xu, Rong-Rong Yuan, Xiao-Rong Chen, Hui-Xian Ma, Ying-Xiao Zhu, Jin-Kai Sun, Fan Yi, Zhe-Yu Chen, Yue Wang
Histone acetylation, which comprises an epigenetic modification, plays an important role in long-term memory formation. Recently, histone deacetylase (HDAC) inhibitors were demonstrated to promote memory formation, which raises the intriguing possibility that HDAC inhibitors may be used to rescue memory deficits. However, additional research is necessary to clarify the roles of individual HDACs in memory. In this study, we demonstrated that HDAC7, within the dorsal hippocampus (DH) of C57BL6J mice, had a late and persistent decrease after contextual fear conditioning (CFC) training (4 h∼24 h), which was involved in long-term CFC memory formation...
March 10, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28273064/class-iia-hdac-inhibition-reduces-breast-tumours-and-metastases-through-anti-tumour-macrophages
#10
Jennifer L Guerriero, Alaba Sotayo, Holly E Ponichtera, Jessica A Castrillon, Alexandra L Pourzia, Sara Schad, Shawn F Johnson, Ruben D Carrasco, Suzan Lazo, Roderick T Bronson, Scott P Davis, Mercedes Lobera, Michael A Nolan, Anthony Letai
Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success...
March 8, 2017: Nature
https://www.readbyqxmd.com/read/28271209/tgf-%C3%AE-1-impairs-mechanosensation-of-human-osteoblasts-via-hdac6-mediated-shortening-and-distortion-of-primary-cilia
#11
Sabrina Ehnert, Vrinda Sreekumar, Romina H Aspera-Werz, Sahar O Sajadian, Elke Wintermeyer, Gunther H Sandmann, Christian Bahrs, Jan G Hengstler, Patricio Godoy, Andreas K Nussler
Transforming growth factor β (TGF-β) is a critical regulator of bone density owing to its multiple effects on cell growth and differentiation. Recently, we have shown that TGF-β1 effectively blocks bone morphogenetic protein (BMP) induced maturation of osteoblasts by upregulating histone deacetylase (HDAC) activity. The current study aimed at investigating the effect of rhTGF-β1 treatment on the expression of specific HDACs and their cellular effects, e.g., microtubule structures (primary cilia) and mechanosensation...
March 7, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28270022/a-phase-1-trial-of-the-hdac-inhibitor-ar-42-in-patients-with-multiple-myeloma-and-t-and-b-cell-lymphomas
#12
Douglas W Sborov, Alessandro Canella, Erinn M Hade, Xiaokui Mo, Soun Khountham, Jiang Wang, Wenjun Ni, Ming Poi, Christopher Coss, Zhongfa Liu, Mitch A Phelps, Amir Mortazavi, Leslie Andritsos, Robert A Baiocchi, Beth A Christian, Don M Benson, Joseph Flynn, Pierluigi Porcu, John C Byrd, Flavia Pichiorri, Craig C Hofmeister
Histone deacetylase inhibitors (HDACi) have proven activity in hematologic malignancies, and their FDA approval in multiple myeloma (MM) and T-cell lymphoma highlights the need for further development of this drug class. We investigated AR-42, an oral pan-HDACi, in a first-in-man phase 1 dose escalation clinical trial. Overall, treatment was well tolerated, no DLTs were evident, and the MTD was defined as 40 mg dosed three times weekly for three weeks of a 28-day cycle. One patient each with MM and mantle cell lymphoma demonstrated disease control for 19 and 27 months (ongoing), respectively...
March 7, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28267674/the-effects-of-saha-on-radiosensitivity-in-pancreatic-cancer-cells-by-inducing-apoptosis-and-targeting-rad51
#13
Zhibing Wu, Saisai Jing, Yanhong Li, Yabo Gao, Shuhuan Yu, Zhitian Li, Yanyan Zhao, Jigang Piao, Shenglin Ma, Xufeng Chen
Suberoyl anilide hydroxamic acid (SAHA) is one of the most promising Histone deacetylases(HDAC) inhibitors which has shown significant anti-tumor activity for many malignancies. We explored the potential mechanism of the radiosensitivity effect of SAHA in Panc-1 cells and attempted to develop SAHA as a systemic treatment strategy for pancreatic cancer. Growth inhibition was detected by CCK-8 assay. Radiosensitizing enhancement ratio was determined by clonogenic assay. The cell cycle and apoptosis assay was detected using flow cytometry and annexin-V/PI...
March 3, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28267067/hdac6-inhibition-effectively-reverses-chemotherapy-induced-peripheral-neuropathy
#14
Karen Krukowski, Jiacheng Ma, Olga Golonzhka, Geoffroy O Laumet, Tanuja Gutti, John H van Duzer, Ralph Mazitschek, Matthew B Jarpe, Cobi J Heijnen, Annemieke Kavelaars
Chemotherapy-induced peripheral neuropathy is one of the most common doselimiting side-effects of cancer treatment. Currently, there is no FDA-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of á-tubulin-dependent intracellular mitochondrial transport. Here we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 versus other HDACs...
March 4, 2017: Pain
https://www.readbyqxmd.com/read/28264055/enhancement-of-pomalidomide-anti-tumor-response-with-acy-241-a-selective-hdac6-inhibitor
#15
Brian J North, Ingrid Almeciga-Pinto, David Tamang, Min Yang, Simon S Jones, Steven N Quayle
Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies...
2017: PloS One
https://www.readbyqxmd.com/read/28262837/inhibiting-histone-deacetylases-suppresses-glucose-metabolism-and-hepatocellular-carcinoma-growth-by-restoring-fbp1-expression
#16
Jing Yang, Xin Jin, Yuqian Yan, Yingjie Shao, Yunqian Pan, Lewis R Roberts, Jun Zhang, Haojie Huang, Jingting Jiang
Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the world. Elevated glucose metabolism in the availability of oxygen, a phenomenon called the Warburg effect, is important for cancer cell growth. Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and is frequently lost in various types of cancer. Here, we demonstrated that expression of FBP1 was downregulated in HCC patient specimens and decreased expression of FBP1 associated with poor prognosis. Low expression of FBP1 correlated with high levels of histone deacetylase 1 (HDAC1) and HDAC2 proteins in HCC patient tissues...
March 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28259626/perfluorinated-hydroxamic-acids-are-potent-and-selective-inhibitors-of-hdac-like-enzymes-from-pseudomonas-aeruginosa
#17
Christian Meyners, Benjamin Wolff, Alexander Kleinschek, Andreas Krämer, Franz-Josef Meyer-Almes
A series of perfluorinated SAHA (PFSAHA) was prepared and profiled against a panel of human and bacterial members of the Histone deacetylase (HDAC) family. Some of the active substances show nanomolar inhibitory activity and several hundred fold selectivity for the HDAC like enzyme PA3774 from P. aeruginosa. The extraordinary selectivity against human HDACs results from the distinct oligomeric state of PA3774 which consists of two head-to-head dimers. The binding pocket is defined by the surface of both opposite monomers confining the access of ligands to the active site...
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28255755/epigenetics-a-link-between-addiction-and-social-environment
#18
REVIEW
Duyilemi C Ajonijebu, Oualid Abboussi, Vivienne A Russell, Musa V Mabandla, William M U Daniels
The detrimental effects of drug abuse are apparently not limited to individuals but may also impact the vulnerability of their progenies to develop addictive behaviours. Epigenetic signatures, early life experience and environmental factors, converge to influence gene expression patterns in addiction phenotypes and consequently may serve as mediators of behavioural trait transmission between generations. The majority of studies investigating the role of epigenetics in addiction do not consider the influence of social interactions...
March 2, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28250687/novel-hydroxamates-potentiated-in-vitro-activity-of-fluconazole-against-candida-albicans
#19
Maneesh Paul-Satyaseela, Periasamy Hariharan, Thirunavukkarasu Bharani, Jonathan S Franklyne, Thangapazham Selvakumar, Kuppusamy Bharathimohan, Chenniappan Vinoth Kumar, Virendra Kachhadia, Shridhar Narayanan, Sridharan Rajagopal, Gopalan Balasubramanian
A set of 12 novel hydroxamate compounds (NHCs), structurally designed as inhibitors of histone deacetylase (HDAC) enzyme, were synthesized at our facility. These were adamantane derivatives with N-hydroxyacetamide as pharmacophore, and each of these compounds was tested for potentiating activity on fluconazole. The concentration of fluconazole which completely inhibited (concentration of complete inhibition [CCI]) the growth of Candida albicans ATCC 90028 and C. albicans ATCC 64550 was determined by micro-dilution method in the absence and presence of NHCs...
January 2017: Journal of Natural Science, Biology, and Medicine
https://www.readbyqxmd.com/read/28249907/hdac-inhibitor-panobinostat-engages-host-innate-immune-defenses-to-promote-the-tumoricidal-effects-of-trastuzumab-in-her2-tumors
#20
Mikolaj Medon, Eva Vidacs, Stephin J Vervoort, Jason Li, Misty R Jenkins, Kelly M Ramsbottom, Joseph A Trapani, Mark J Smyth, Phillip K Darcy, Peter W Atadja, Michael A Henderson, Ricky W Johnstone, Nicole M Haynes
Histone deacetylase inhibitors (HDACi) may engage host immunity as one basis for their antitumor effects. Herein we demonstrate an application of this concept using the HDACi panobinostat to augment the antitumor efficacy of trastuzumab (anti-HER2) therapy, through both tumor cell autonomous and non-autonomous mechanisms. In HER2+ tumors that are inherently sensitive to the cytostatic effects of trastuzumab, co-treatment with panobinostat abrogated AKT signaling and triggered tumor regression in mice that lacked innate and/or adaptive immune effector cells...
March 1, 2017: Cancer Research
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