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Vorinostat

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https://www.readbyqxmd.com/read/28537899/nras-mutations-in-cutaneous-t-cell-lymphoma-ctcl-sensitize-tumors-towards-treatment-with-the-multikinase-inhibitor-sorafenib
#1
Michael K Kießling, Jan P Nicolay, Tabea Schlör, Claus-Detlev Klemke, Dorothee Süss, Peter H Krammer, Karsten Gülow
Therapy of cutaneous T cell lymphoma (CTCL) is complicated by a distinct resistance of the malignant T cells towards apoptosis that can be caused by NRAS mutations in late-stage patients. These mutations correlate with decreased overall survival, but sensitize the respective CTCL cells towards MEK-inhibition-induced apoptosis which represents a promising novel therapeutic target in CTCL. Here, we show that the multi-kinase inhibitor Sorafenib induces apoptosis in NRAS-mutated CTCL cells. CTCL cell lines and to a minor extent primary T cells from Sézary patients without NRAS mutations are also affected by Sorafenib-induced apoptosis suggesting a sensitizing role of NRAS mutations for Sorafenib-induced apoptosis...
May 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28537897/mek-inhibitors-cobimetinib-and-trametinib-regressed-a-gemcitabine-resistant-pancreatic-cancer-patient-derived-orthotopic-xenograft-pdox
#2
Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Tasuku Kiyuna, Thinzar M Lwin, Ho Kyoung Hwang, Jonathan C Delong, Bryan M Clary, Michael Bouvet, Michiaki Unno, Robert M Hoffman
A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p...
May 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28535287/a-flow-cytometry-based-screen-identifies-mbnl1-modulators-that-rescue-splicing-defects-in-myotonic-dystrophy-type-i
#3
Fan Zhang, Nicole E Bodycombe, Keith M Haskell, Yumei L Sun, Eric T Wang, Carl A Morris, Lyn H Jones, Lauren D Wood, Mathew T Pletcher
Myotonic Dystrophy Type 1 (DM1) is a rare genetic disease caused by expansion of CTG trinucleotide repeats ((CTG)exp) in the 3' untranslated region of the DMPK gene. The repeat transcripts sequester the RNA binding protein Muscleblind-like protein 1 (MBNL1) and hamper its normal function in pre-mRNA splicing. Overexpressing exogenous MBNL1 in the DM1 mouse model has been shown to rescue the splicing defects and reverse myotonia. Although a viable therapeutic strategy, pharmacological modulators of MBNL1 expression have not been identified...
May 23, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28530797/unexpected-biotransformation-of-the-hdac-inhibitor-vorinostat-yields-aniline-containing-fungal-metabolites
#4
Donovon A Adpressa, Kayla J Stalheim, Philip Jerome Proteau, Sandra Loesgen
The diversity of genetically encoded small molecules produced by filamentous fungi remains largely unexplored, which makes these fungi an attractive source for the discovery of new compounds. However, accessing their full chemical repertoire under common laboratory culture conditions is a challenge. Epigenetic manipulation of gene expression has become a well-established tool for overcoming this obstacle. Here we report that perturbation of the endophytic ascomycete Chalara sp. 6661, producer of the isofusidienol class of antibiotics, with the HDAC inhibitor vorinostat resulted in the production of four new modified xanthones...
May 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28486043/randomized-phase-ii-study-of-azacitidine-alone-or-in-combination-with-lenalidomide-or-with-vorinostat-in-higher-risk-myelodysplastic-syndromes-and-chronic-myelomonocytic-leukemia-north-american-intergroup-study-swog-s1117
#5
Mikkael A Sekeres, Megan Othus, Alan F List, Olatoyosi Odenike, Richard M Stone, Steven D Gore, Mark R Litzow, Rena Buckstein, Min Fang, Diane Roulston, Clara D Bloomfield, Anna Moseley, Aziz Nazha, Yanming Zhang, Mario R Velasco, Rakesh Gaur, Ehab Atallah, Eyal C Attar, Elina K Cook, Alyssa H Cull, Michael J Rauh, Frederick R Appelbaum, Harry P Erba
Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m(2)/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9)...
May 9, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28454309/targeting-cd146-in-combination-with-vorinostat-for-the-treatment-of-ovarian-cancer-cells
#6
Xiaoli Ma, Jiandong Wang, Jia Liu, Qingqing Mo, Xiyun Yan, Ding Ma, Hua Duan
Drug resistance is the predominant cause of mortality in late-stage patients with ovarian cancer. Histone deacetylase inhibitors (HDACis) have emerged as a novel type of second line drug with high specificity for tumor cells, including ovarian cancer cells. However, HDACis usually exhibit relatively low potencies when used as a single agent. The majority of current clinical trials are combination strategies. These strategies are more empirical than mechanism-based applications. Previously, it was reported that the adhesion molecule cluster of differentiation 146 (CD146) is significantly induced in HDACi-treated tumor cells...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28425177/design-and-synthesis-of-c3-substituted-%C3%AE-carboline-based-histone-deacetylase-inhibitors-with-potent-antitumor-activities
#7
Yong Ling, Jiao Feng, Lin Luo, Jing Guo, Yanfu Peng, Tingting Wang, Xiang Ge, Qibing Xu, Xinyang Wang, Hong Dai, Yanan Zhang
A series of hydroxamic acid histone deacetylase (HDAC) inhibitors in which the β-carboline motif has been incorporated were designed and synthesized. The effect of substitution at the C3 amide on HDAC inhibition and antiproliferative activities was investigated. Most of these compounds were found to display significant HDAC inhibitory effects and good antiproliferative activity, with IC50 values in the low-micromolar range. In particular, the HDAC inhibition IC50 value of N-(2-(dimethylamino)ethyl)-N-(4-(hydroxylcarbamoyl)benzyl)-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (9 h) is five-fold lower than that of suberoylanilide hydroxamic acid (SAHA, vorinostat)...
April 20, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28415633/a-phase-2-study-of-vorinostat-in-locally-advanced-recurrent-or-metastatic-adenoid-cystic-carcinoma
#8
Priscila H Goncalves, Lance K Heilbrun, Michael T Barrett, Shivaani Kummar, Aaron R Hansen, Lillian L Siu, Richard L Piekarz, Ammar W Sukari, Joseph Chao, Mary Jo Pilat, Daryn W Smith, Lindsay Casetta, Scott A Boerner, Alice Chen, Elizabeth Lenkiewicz, Smriti Malasi, Patricia M LoRusso
PURPOSE: Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial. METHODS: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients. RESULTS: Thirty patients were enrolled...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28398261/novel-proteasome-inhibitors-and-histone-deacetylase-inhibitors-progress-in-myeloma-therapeutics
#9
REVIEW
Saurabh Chhabra
The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the chaperone system. If this process fails, the misfolded proteins have to be eliminated by the two main garbage-disposal systems of the cell: proteasome and aggresome. The blockade of either of these systems will result in accumulation of immunoglobulins and other toxic proteins in the cytoplasm and cell death...
April 11, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28371677/design-synthesis-and-biological-evaluation-of-quinoline-derivatives-as-hdac-class-i-inhibitors
#10
Chen Chen, Xuben Hou, Guohua Wang, Wenyan Pan, Xinying Yang, Yingkai Zhang, Hao Fang
Inhibition of histone deacetylase (HDAC) has been regarded as a potential therapeutic approach for treatment of multiple diseases including cancer. Based on pharmacophore model of HDAC inhibitors, a series of quinoline-based N-hydroxycinnamamides and N-hydroxybenzamides were designed and synthesized as potent HDAC inhibitors. All target compounds were evaluated for their in vitro HDAC inhibitory activities and anti-proliferative activities and the best compound 4a surpass Vorinostat in both enzymatic inhibitory activity and cellular anti-proliferative activity...
March 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28352654/net-silencing-by-let-7i-in-postural-tachycardia-syndrome
#11
Abdul Waheed Khan, Mark Ziemann, Susan J Corcoran, Harikrishnan K N, Jun Okabe, Haloom Rafehi, Scott S Maxwell, Murray D Esler, Assam El-Osta
While strongly implicated in postural tachycardia syndrome (POTS), considerable controversy exists regarding norepinephrine transporter (NET) loss of function. POTS is characterized by the clinical symptoms of orthostatic intolerance, lightheadedness, tachycardia, and syncope or near syncope with upright posture. Abnormal sympathetic nervous system activity is typical, of a type which suggests dysfunction of the NET, with evidence that the gene responsible is under tight epigenetic control. Using RNA of isolated chromatin combined with massive parallel sequencing (RICh-seq) we show that let-7i miRNA suppresses NET by methyl-CpG-binding protein 2 (MeCP2)...
March 23, 2017: JCI Insight
https://www.readbyqxmd.com/read/28339982/a-morphoproteomic-study-of-metformin-and-vorinostat-alone-and-in-combination-induced-apoptosis-in-molt-4-acute-leukemia-cells
#12
Anneliese Velez-Perez, Robert E Brown, Amitava Dasgupta, Priya Weerasinghe
No abstract text is available yet for this article.
March 1, 2017: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28337317/structural-requirements-of-hdac-inhibitors-saha-analogues-modified-at-the-c2-position-display-hdac6-8-selectivity
#13
Ahmed T Negmeldin, Geetha Padige, Anton V Bieliauskas, Mary Kay H Pflum
Histone deacetylase (HDAC) proteins are epigenetic regulators that deacetylate protein substrates, leading to subsequent changes in cell function. HDAC proteins are implicated in cancers, and several HDAC inhibitors have been approved by the FDA as anticancer drugs, including SAHA (suberoylanilide hydroxamic acid; Vorinostat and Zolinza). Unfortunately, SAHA inhibits most HDAC isoforms, which limits its use as a pharmacological tool and may lead to side effects in the clinic. In this work SAHA analogues substituted at the C2 position were synthesized and screened for HDAC isoform selectivity in vitro and in cells...
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28317157/design-and-synthesis-of-novel-anti-plasmodial-histone-deacetylase-inhibitors-containing-an-alkoxyamide-connecting-unit
#14
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...
April 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
#15
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...
June 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28314266/additive-interaction-of-cisplatin-and-histone-deacetylase-inhibitors-combined-treatment-in-rhabdomyosarcoma-cells-an-isobolographic-analysis
#16
Agata Jarząb, Jarogniew J Łuszczki, Małgorzata Guz, Ewelina Gumbarewicz, Krzysztof Polberg, Andrzej Stepulak
BACKGROUND/AIM: The aim of this study was to assess the anticancer effect and the type of pharmacologic drug-drug interaction of cisplatin (CDDP) and histone deacetylase inhibitors (HDIs) combined treatment on the rhabdomyosarcoma cell line. MATERIALS AND METHODS: The antiproliferative actions of cisplatin and suberoylanilide hydroxamic acid (SAHA, vorinostat), as well as valproic acid (VPA) alone and in combination, were evaluated using the tetrazolium dye-based MTT cell proliferation assay and isobolographic analysis...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28301423/no-adverse-safety-or-virological-changes-2-years-following-vorinostat-in-hiv-infected-individuals-on-antiretroviral-therapy
#17
Talia M Mota, Thomas A Rasmussen, Ajantha Rhodes, Surekha Tennakoon, Ashanti Dantanarayana, Fiona Wightman, Michelle Hagenauer, Janine Roney, Tim Spelman, Damian F J Purcell, James McMahon, Jennifer F Hoy, H Miles Prince, Julian H Elliott, Sharon R Lewin
OBJECTIVE: To determine the long-term effects of vorinostat on safety and virological parameters in HIV-infected individuals on suppressive antiretroviral therapy (ART). DESIGN: Prospective longitudinal observational extended follow-up of 20 HIV-infected individuals on ART previously enrolled in a clinical trial of daily vorinostat 400 mg for 14 days. Extended follow-up included visits at 6, 12, 18 and 24 months postenrolment in the initial clinical trial. METHODS: Cell-associated unspliced HIV RNA, total HIV DNA and plasma HIV RNA were quantified by PCR, and CD4 and CD8 T cells quantified by flow cytometry...
May 15, 2017: AIDS
https://www.readbyqxmd.com/read/28273193/-drug-therapy-of-lymphomas
#18
Lajos Gergely
The therapy of lymphomas has undergone a major expansion during the last decade. Novel therapeutic targets have appeared beyond classical chemotherapeutic combinations. These novel drugs have very pronounced action across lymphoma types, and their toxicity profile is usually better tolerable compared to standard chemotherapies. These new therapies are enabling us to offer treatment to those patients who have refractory disease, and we had no option to treat them before these drugs. The author describes several new therapeutic options...
March 8, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28222071/combination-of-the-histone-deacetylase-inhibitor-vorinostat-with-bevacizumab-in-patients-with-clear-cell-renal-cell-carcinoma-a-multicentre-single-arm-phase-i-ii-clinical-trial
#19
MULTICENTER STUDY
Roberto Pili, Glenn Liu, Sreenivasulu Chintala, Hendrick Verheul, Shabnam Rehman, Kristopher Attwood, Martin A Lodge, Richard Wahl, James I Martin, Kiersten Marie Miles, Silvia Paesante, Remi Adelaiye, Alejandro Godoy, Serina King, James Zwiebel, Michael A Carducci
BACKGROUND: Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus...
March 28, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28208023/transcriptomic-profiling-of-human-hippocampal-progenitor-cells-treated-with-antidepressants-and-its-application-in-drug-repositioning
#20
Timothy R Powell, Tytus Murphy, Sang H Lee, Jack Price, Sandrine Thuret, Gerome Breen
Current pharmacological treatments for major depressive disorder (MDD) are ineffective in a significant proportion of patients, and the identification of new antidepressant compounds has been difficult. 'Connectivity mapping' is a method that can be used to identify drugs that elicit similar downstream effects on mRNA levels when compared to current treatments, and thus may point towards possible repositioning opportunities. We investigated genome-wide transcriptomic changes to human hippocampal progenitor cells treated with therapeutically relevant concentrations of a tricyclic antidepressant (nortriptyline) and a selective serotonin reuptake inhibitor (escitalopram)...
March 2017: Journal of Psychopharmacology
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