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https://www.readbyqxmd.com/read/28819699/cudc-907-a-dual-hdac-and-pi3k-inhibitor-reverses-platinum-drug-resistance
#1
Kenneth K W To, Li-Wu Fu
Platinum (Pt)-based anticancer drugs are the mainstay of treatment for solid cancers. However, resistance to Pt drugs develops rapidly, which can be caused by overexpression of multidrug resistance transporters and activation of DNA repair. CUDC-907 is a potent molecular targeted anticancer agent, rationally designed to simultaneously inhibit histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K). We investigated the potentiation effect of CUDC-907 on Pt drugs in resistant cancer cells. ABCC2 stably-transfected HEK293 cells and two pairs of parental and Pt-resistant cancer cell lines were used to test for the circumvention of resistance by CUDC-907...
August 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28819166/histone-protein-deacetylase-11-targeting-promotes-foxp3-treg-function
#2
Jianbing Huang, Liqing Wang, Satinder Dahiya, Ulf H Beier, Rongxiang Han, Arabinda Samanta, Joel Bergman, Eduardo M Sotomayor, Edward Seto, Alan P Kozikowski, Wayne W Hancock
Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28818449/rational-design-synthesis-and-preliminary-antitumor-activity-evaluation-of-a-chlorambucil-derivative-with-potent-dna-hdac-dual-targeting-inhibitory-activity
#3
Rui Xie, Yan Li, Pingwah Tang, Qipeng Yuan
Histone deacetylases (HDACs) play a pivotal role not only in gene expression but also in DNA repair. Herein, we report the successful design, synthesis and evaluation of a chlorambucil derivative named vorambucil with a hydroxamic acid tail as a DNA/HDAC dual-targeting inhibitor. Vorambucil obtained both potent DNA and HDACs inhibitory activities. Molecular docking results supported the initial pharmacophoric hypothesis and rationalized the potent inhibitory activity of vorambucil against HDAC1, HDAC2 and HDAC6...
August 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28814980/cooperative-effect-of-chidamide-and-chemotherapeutic-drugs-induce-apoptosis-by-dna-damage-accumulation-and-repair-defects-in-acute-myeloid-leukemia-stem-and-progenitor-cells
#4
Yin Li, Yan Wang, Yong Zhou, Jie Li, Kai Chen, Leisi Zhang, Manman Deng, Suqi Deng, Peng Li, Bing Xu
BACKGROUND: Many conventional chemotherapeutic drugs are known to be involved in DNA damage, thus ultimately leading to apoptosis of leukemic cells. However, they fail to completely eliminate leukemia stem cells (LSCs) due to their higher DNA repair capacity of cancer stem cells than that of bulk cancer cells, which becomes the root of drug resistance and leukemia recurrence. A new strategy to eliminate LSCs in acute myeloid leukemia (AML) is therefore urgently needed. RESULTS: We report that a low-dose chidamide, a novel orally active benzamide-type histone deacetylase (HDAC) inhibitor, which selectively targets HDACs 1, 2, 3, and 10, could enhance the cytotoxicity of DNA-damaging agents (daunorubicin, idarubicin, and cytarabine) in CD34(+)CD38(-) KG1α cells, CD34(+)CD38(-) Kasumi cells, and primary refractory or relapsed AML CD34(+) cells, reflected by the inhibition of cell proliferation, induction of apoptosis, and increase of cell cycle arrest in vitro...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28814661/hdac-inhibition-induces-hiv-1-protein-and-enables-immune-based-clearance-following-latency-reversal
#5
Guoxin Wu, Michael Swanson, Aarthi Talla, Donald Graham, Julie Strizki, Daniel Gorman, Richard Jo Barnard, Wade Blair, Ole S Søgaard, Martin Tolstrup, Lars Østergaard, Thomas A Rasmussen, Rafick-Pierre Sekaly, Nancie M Archin, David M Margolis, Daria J Hazuda, Bonnie J Howell
Promising therapeutic approaches for eradicating HIV include transcriptional activation of provirus from latently infected cells using latency-reversing agents (LRAs) and immune-mediated clearance to purge reservoirs. Accurate detection of cells capable of producing viral antigens and virions, and the measurement of clearance of infected cells, is essential to assessing therapeutic efficacy. Here, we apply enhanced methodology extending the sensitivity limits for the rapid detection of subfemtomolar HIV gag p24 capsid protein in CD4+ T cells from ART-suppressed HIV+ individuals, and we show viral protein induction following treatment with LRAs...
August 17, 2017: JCI Insight
https://www.readbyqxmd.com/read/28812434/-pemetrexed-sildenafil-via-autophagy-dependent-hdac-down-regulation-enhances-the-immunotherapy-response-of-nsclc-cells
#6
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
Pemetrexed is an approved therapeutic in NSCLC and ovarian cancer. Our studies focused on the ability of [pemetrexed + sildenafil] exposure to alter the immunogenicity of lung and ovarian cancer cells. Treatment of lung and ovarian cancer cells with [pemetrexed + sildenafil] in vitro rapidly reduced the expression of PD-L1, PD-L2 and ornithine decarboxylase (ODC), and increased the expression of Class I MHCA. In a cell-specific fashion, some cells also released the immunogenic nuclear protein HMGB1 into the extracellular environment...
August 16, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28812327/design-and-synthesis-of-terephthalic-acid-based-histone-deacetylase-inhibitors-with-dual-stage-anti-plasmodium-activity
#7
Katharina Stenzel, Ming Jang Chua, Sandra Duffy, Yevgeniya Antonova-Koch, Stephan Meister, Alexandra Hamacher, Matthias U Kassack, Elizabeth A Winzeler, Vicky M Avery, Thomas Kurz, Katherine T Andrews, Finn Kristian Hansen
In this work we aimed to develop parasite-selective HDAC inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis and biological testing of a series of 13 terephthalic acid-based histone deacetylase inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC50 8 - >51 µM), with 11 also having sub-micromolar in vitro activity against drug-sensitive (3D7) and multi-drug resistant (Dd2) asexual blood stage Plasmodium falciparum parasites (IC50 ~ 0...
August 15, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28812060/reolysin-and-histone-deacetylase-inhibition-in-the-treatment-of-head-and-neck-squamous-cell-carcinoma
#8
Alena C Jaime-Ramirez, Jun-Ge Yu, Enrico Caserta, Ji Young Yoo, Jianying Zhang, Tae Jin Lee, Craig Hofmeister, John H Lee, Bhavna Kumar, Quintin Pan, Pawan Kumar, Robert Baiocchi, Theodoros Teknos, Flavia Pichiorri, Balveen Kaur, Matthew Old
Oncolytic viruses (OVs) are emerging as powerful anti-cancer agents and are currently being tested for their safety and efficacy in patients. Reovirus (Reolysin), a naturally occurring non-pathogenic, double-stranded RNA virus, has natural oncolytic activity and is being tested in phase I-III clinical trials in a variety of tumor types. With its recent US Food and Drug Administration (FDA) orphan drug designation for several tumor types, Reolysin is a potential therapeutic agent for various cancers, including head and neck squamous cell carcinomas (HNSCCs), which have a 5-year survival of ∼55%...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28809557/in-silico-and-in-vitro-interactions-between-short-chain-fatty-acids-and-human-histone-deacetylases
#9
Rou Hui Ho, James Chun Yip Chan, Hao Fan, Dorinda Yan Qin Kioh, Bee Wah Lee, Eric Chun Yong Chan
Short chain fatty acids (SCFAs) are postulated to modulate the immune development of neonates via epigenetic regulations such as histone deacetylase (HDAC) inhibition. In the context of atopic diseases, the inhibition of HDAC maintains T-cell homeostasis and induces naïve T-cell differentiation into adaptive Treg, which regulates the production of anti-inflammatory cytokines and suppression of Th2 immune responses. We investigated the structure-inhibition relationships of SCFAs with class I HDAC3 and class IIa HDAC7 using in silico docking simulation and in vitro human recombinant HDAC inhibition assay...
August 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/28808995/high-resolution-parallel-reaction-monitoring-with-electron-transfer-dissociation-for-middle-down-proteomics-an-application-to-study-the-quantitative-changes-induced-by-histone-modifying-enzyme-inhibitors-and-activators
#10
Michael J Sweredoski, Annie Moradian, Sonja Hess
With the advent of new methodologies, proteomics-based assays are increasingly used to study the efficacy of drugs on a molecular level. For these studies to be meaningful, the proteomics assays need to be sensitive, selective, accurate, and reproducible. This is often accomplished through a targeted approach, either using single or multiple reaction monitoring (SRM/MRM) or, more recently, parallel reaction monitoring (PRM). In PRM, the parallel detection of all product ions in a high-resolution mass spectrometer affords higher selectivity than SRM/MRM...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28805377/intrinsic-dynamics-of-binding-rail-and-its-allosteric-effect-in-the-class-i-hdacs
#11
Jingwei Zhou, Yue Huang, Chunyan Cheng, Kai Wang, Ruibo Wu
The development of novel isoform/class-selective inhibitor is still of great biological and medical significance to conquer the continuously reported side effects for the histone deacetylases (HDACs) drugs. The first potent HDAC allosteric inhibitor was discovered last year and this allosteric inhibitor design is thought to be a promising strategy to overcome the current challenges in HDAC inhibitor design. However, the detailed allosteric mechanisms and its remote regulation effects on the catalytic/inhibitor activity of HDAC are still unclear...
August 14, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28796285/inhibition-of-histone-deacetylase-1-or-2-reduces-induced-cytokine-expression-in-microglia-through-a-protein-synthesis-independent-mechanism
#12
Benjamin S Durham, Ronald Grigg, Ian C Wood
Histone deacetylase (HDAC) inhibitors prevent neural cell death in in vivo models of cerebral ischaemia, brain injury and neurodegenerative disease. One mechanism by which HDAC inhibitors may do this is by suppressing the excessive inflammatory response of chronically activated microglia. However, the molecular mechanisms underlying this anti-inflammatory effect and the specific HDAC responsible are not fully understood. Recent data from in vivo rodent studies has shown that inhibition of class I HDACs suppresses neuroinflammation and is neuroprotective...
August 10, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28782836/histone-deacetylase-3-deletion-in-mesenchymal-progenitor-cells-hinders-long-bone-development
#13
Marina Feigenson, Lomeli Carpio Shull, Earnest L Taylor, Emily T Camilleri, Scott M Reister, Andre J van Wijnen, Elizabeth W Bradley, Jennifer J Westendorf
Long bone formation is a complex process that requires precise transcriptional control of gene expression programs in mesenchymal progenitor cells. Histone deacetylases (Hdacs) coordinate chromatin structure and gene expression by enzymatically removing acetyl groups from histones and other proteins. Hdac inhibitors are used clinically to manage mood disorders, cancers and other conditions, but are teratogenic to the developing skeleton and increase fracture risk in adults. In this study, the functions of Hdac3, one of the enzymes blocked by current Hdac inhibitor therapies, in skeletal mesenchymal progenitor cells were determined...
August 7, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28776290/synthesis-characterization-and-evaluation-of-cd-l-proline-2-a-novel-histone-deacetylase-inhibitor-that-induces-epigenetic-modification-of-histone-deacetylase-isoforms-in-a549-cells
#14
Anusha Chidambaram, Arunachalam Sekar, Kavya S H, Ramesh Kumar Chidambaram, Kalaiarasi Arunachalam, Senthilkumar G P, Ravikumar Vilwanathan
Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression through their effects on the compact chromatin structure. In clinical studies, several classes of histone deacetylase inhibitors (HDACi) have demonstrated potent anticancer activities with metal complexes. Hence, we synthesized cadmium-proline complexes using both the D- and L-isomers of proline and evaluated their biological activities by observing the efficiency of their inhibition of HDAC activity, ability to reduce the expression of HDAC isoforms in A549 cells and effect on apoptosis...
August 3, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28771357/class-i-hdac-inhibitors-potential-new-epigenetic-therapeutics-for-alcohol-use-disorder-aud
#15
Erika Bourguet, Katarzyna Ozdarska, Gautier Moroy, Jérôme Jeanblanc, Mickael Naassila
Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapies is a pressing necessity. Alcohol exposure has been widely demonstrated to modulate epigenetic mechanisms, such as histone acetylation/deacetylation balance, in part via histone deacetylase (HDAC) inhibition. Epigenetic factors have been suggested to play a key role in AUD. To date, 18 different mammalian HDAC isoforms have been identified, and these have been divided into four classes. Since recent studies have suggested that both epigenetic mechanisms underlying AUD and the efficacy of HDAC inhibitors (HDACIs) in different animal models of AUD may involve class I HDACs, we herein report the development of class I HDACIs, including information regarding their structure, potency, and selectivity...
August 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28769891/histone-deacetylase-2-is-a-component-of-influenza-a-virus-induced-host-antiviral-response
#16
Prashanth T Nagesh, Mazhar Hussain, Henry D Galvin, Matloob Husain
Host cells produce variety of antiviral factors that create an antiviral state and target various stages of influenza A virus (IAV) life cycle to inhibit infection. However, IAV has evolved various strategies to antagonize those antiviral factors. Recently, we reported that a member of class I host histone deacetylases (HDACs), HDAC1 possesses an anti-IAV function. Herein, we provide evidence that HDAC2, another class I member and closely related to HDAC1 in structure and function, also possesses anti-IAV properties...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28767685/histone-deacetylase-inhibition-prevents-cell-death-induced-by-loss-of-tricellular-tight-junction-proteins-in-temperature-sensitive-mouse-cochlear-cells
#17
Kenichi Takano, Takuya Kakuki, Yakuto Kaneko, Takayuki Kohno, Shin Kikuchi, Tetsuo Himi, Takashi Kojima
Tricellular tight junctions (tTJs) are specialized structures that occur where the corners of three cells meet to seal adjacent intercellular space. The molecular components of tTJs include tricellulin (TRIC) and lipolysis-stimulated lipoprotein receptor (LSR) which recruits TRIC, are required for normal hearing. Although loss of TRIC causes hearing loss with degeneration of cochlear cells, the detailed mechanisms remains unclear. In the present study, by using temperature-sensitive mouse cochlear cells, US/VOT-E36 cell line, we investigated the changes of TRIC and LSR during cochlear cell differentiation and the effects of histone deacetylase (HDAC) inhibitors against cell degeneration induced by loss of TRIC and LSR...
2017: PloS One
https://www.readbyqxmd.com/read/28765013/structure-based-design-synthesis-and-in-vitro-antiproliferative-effects-studies-of-novel-dual-brd4-hdac-inhibitors
#18
Mingfeng Shao, Linhong He, Li Zheng, Lingxiao Huang, Yuanyuan Zhou, Taijing Wang, Yong Chen, Mingsheng Shen, Fang Wang, Zhuang Yang, Lijuan Chen
Histone acetylation marks play important roles in controlling gene expressions and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins, whose targeted inhibitors are under clinical investigation. BET and HDAC inhibitors have been demonstrated to be synergistically killing in Mycinduced murine lymphoma. Herein, we combine the inhibitory activities of BET and HDAC into one molecule through structure-based design method and evaluate its function. The majority of these synthesized compounds showed inhibitory activity against second bromdomains(BRD) of BRD4 and HDAC1...
July 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28762309/histone-deacetylase-inhibitors-in-tumor-immunotherapy
#19
Li-Ming Zhao, Jie-Huan Zhang
With an increasing understanding of the antitumor immune response, considerable progress has been made in the field of tumor immunotherapy in the last decade. Inhibition of HDACs represents a new strategy in tumor therapy and HDAC inhibitors have been recently developed and validated as potential antitumor drugs. In addition to the direct antitumor effects, HDAC inhibitors have been found to have the ability to improve tumor recognition by immune cells that may contribute to their antitumor activity. These immunomodolutory effects are desirable, and their in-depth comprehension will facilitate the design of novel regimens with improved clinical efficacy...
August 1, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28760302/developmental-therapeutics-in-myeloproliferative-neoplasms
#20
REVIEW
Prithviraj Bose, Srdan Verstovsek
The unprecedented success of the Janus kinase (JAK) 1/2 inhibitor ruxolitinib in myelofibrosis (MF) provided much-needed impetus for clinical drug development for the Philadelphia chromosome-negative myeloproliferative neoplasms. The survival benefit conferred by this agent, along with its marked efficacy with regard to spleen volume and symptom reduction, have made ruxolitinib the cornerstone of drug therapy in MF. However, there remain significant unmet needs in the treatment of patients with MF, and many novel classes of agents continue to be investigated in efforts to build on the progress made with ruxolitinib...
July 2017: Clinical Lymphoma, Myeloma & Leukemia
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