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https://www.readbyqxmd.com/read/29754815/an-acquired-vulnerability-of-drug-resistant-melanoma-with-therapeutic-potential
#1
Liqin Wang, Rodrigo Leite de Oliveira, Sanne Huijberts, Evert Bosdriesz, Nora Pencheva, Diede Brunen, Astrid Bosma, Ji-Ying Song, John Zevenhoven, G Tjitske Los-de Vries, Hugo Horlings, Bastiaan Nuijen, Jos H Beijnen, Jan H M Schellens, Rene Bernards
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells...
April 28, 2018: Cell
https://www.readbyqxmd.com/read/29731425/histone-deacetylase-11-is-an-%C3%AE%C2%B5-n-myristoyllysine-hydrolase
#2
Carlos Moreno-Yruela, Iacopo Galleano, Andreas S Madsen, Christian A Olsen
Histone deacetylase (HDAC) enzymes regulate diverse biological function, including gene expression, rendering them potential targets for intervention in a number of diseases, with a handful of compounds approved for treatment of certain hematologic cancers. Among the human zinc-dependent HDACs, the most recently discovered member, HDAC11, is the only member assigned to subclass IV. It is the smallest protein and has the least well understood biological function. Here, we show that HDAC11 cleaves long-chain acyl modifications on lysine side chains with remarkable efficiency...
April 23, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29721965/primary-rod-and-cone-degeneration-is-prevented-by-hdac-inhibition
#3
Dragana Trifunović, Eleni Petridou, Antonella Comitato, Valeria Marigo, Marius Ueffing, François Paquet-Durand
Photoreceptor cell death in inherited retinal degeneration is accompanied by over-activation of histone deacetylases (HDAC). Excessive HDAC activity is found both in primary rod degeneration (such as in the rd10 mouse) and in primary cone death, including the cone photoreceptor function loss 1 (cpfl1) mouse. We evaluated the potential of pharmacological HDAC inhibition to prevent photoreceptor degeneration in primary rod and cone degeneration. We show that a single in vivo treatment of cpfl1 mice with the HDAC inhibitor trichostatin A (TSA) resulted in a significant protection of cpfl1 mutant cones...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29709701/co-targeting-of-bet-proteins-and-hdacs-as-a-novel-approach-to-trigger-apoptosis-in-rhabdomyosarcoma-cells
#4
Julius C Enßle, Cathinka Boedicker, Marek Wanior, Meike Vogler, Stefan Knapp, Simone Fulda
Histone acetylation marks exert essential functions in regulating gene expression. These marks are written by histone acetyltransferases (HATs), removed by histone deacetylases (HDACs) and read by e.g. BET proteins. While BET inhibitors are promising new anticancer drugs, little is yet known on their antitumor activity in rhabdomyosarcoma (RMS). We therefore investigated the efficacy of the prototypic BET inhibitor JQ1 alone or in combination with other epigenetic modifiers, namely HDAC inhibitors (HDACIs)...
April 27, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29706951/transcriptional-modulation-of-human-endogenous-retroviruses-in-primary-cd4-t-cells-following-vorinostat-treatment
#5
Cory H White, Nadejda Beliakova-Bethell, Steven M Lada, Michael S Breen, Tara P Hurst, Celsa A Spina, Douglas D Richman, John Frater, Gkikas Magiorkinis, Christopher H Woelk
The greatest obstacle to a cure for HIV is the provirus that integrates into the genome of the infected cell and persists despite antiretroviral therapy. A "shock and kill" approach has been proposed as a strategy for an HIV cure whereby drugs and compounds referred to as latency-reversing agents (LRAs) are used to "shock" the silent provirus into active replication to permit "killing" by virus-induced pathology or immune recognition. The LRA most utilized to date in clinical trials has been the histone deacetylase (HDAC) inhibitor-vorinostat...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29674494/safety-and-efficacy-of-vorinostat-bortezomib-doxorubicin-and-dexamethasone-in-a-phase-i-ii-study-for-relapsed-or-refractory-multiple-myeloma-verumm-study-vorinostat-in-elderly-relapsed-and-unfit-multiple-myeloma
#6
Johannes M Waldschmidt, Alexander Keller, Gabriele Ihorst, Olga Grishina, Stefan Müller, Dagmar Wider, Anna V Frey, Kristina King, Roman Simon, Annette May, Pierfrancesco Tassone, Justus Duyster, Manfred Jung, Noopur Raje, Ralph Wäsch, Monika Engelhardt
This phase I/II trial was conducted to investigate the safety, efficacy, and pharmacodynamics of the pan-HDAC-inhibitor (HDACi) vorinostat combined with bortezomib, doxorubicin, and dexamethasone (VBDD) in patients suffering from relapsed/refractory multiple myeloma (RRMM). In the phase I part of this study, 9/33 patients received dose-escalated vorinostat (100, 200, 300mg), using a 4-day-on and 4-day-off schedule, and a standard 3+3 design. In the phase II part of the study, 24/33 patients were included to further assess VBDD's safety and efficacy...
April 19, 2018: Haematologica
https://www.readbyqxmd.com/read/29673366/improving-cytocompatibility-of-cdte-quantum-dots-by-schiff-base-coordinated-lanthanides-surface-doping
#7
Hana Buchtelova, Vladislav Strmiska, Zuzana Skubalova, Simona Dostalova, Petr Michalek, Sona Krizkova, David Hynek, Lukas Kalina, Lukas Richtera, Amitava Moulick, Vojtech Adam, Zbynek Heger
BACKGROUND: Suitable fluorophores are the core of fluorescence imaging. Among the most exciting, yet controversial, labels are quantum dots (QDs) with their unique optical and chemical properties, but also considerable toxicity. This hinders QDs applicability in living systems. Surface chemistry has a profound impact on biological behavior of QDs. This study describes a two-step synthesis of QDs formed by CdTe core doped with Schiff base ligand for lanthanides [Ln (Yb3+ , Tb3+ and Gd3+ )] as novel cytocompatible fluorophores...
April 19, 2018: Journal of Nanobiotechnology
https://www.readbyqxmd.com/read/29668549/epigenetic-therapy-in-a-patient-with-down-syndrome-and-refractory-acute-myeloid-leukemia
#8
Kerri Becktell, Kerri Houser, Michael J Burke
Acute myeloid leukemia (AML) associated with Down syndrome (DS-AML) is a unique entity of AML with superior treatment response and overall survival compared with children with non-DS-AML. Despite good outcomes in DS-AML, those who relapse or have refractory disease have poor survival. Successful treatment of these patients is challenged by increased incidence of treatment-related toxicities often encountered with high-dose chemotherapy. Here we report the experience of epigenetic modifying agents (decitabine and vorinostat) followed by fludarabine, cytarabine, and granulocyte colony stimulating growth factor for a child with refractory DS-AML...
April 17, 2018: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/29667768/quinazoline-based-hydroxamic-acids-design-synthesis-and-evaluation-of-histone-deacetylase-inhibitory-effects-and-cytotoxicity
#9
Doan Thanh Hieu, Duong Tien Anh, Hai Pham-The, Le-Thi-Thu Huong, Eun Jae Park, Jeong Eun Choi, Jong Soon Kang, Sang-Bae Han, Phan Thi Phuong Dung, Nguyen-Hai Nam
In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N-hydroxybenzamides incorporating quinazoline heterocycles (4a-i, 6a-i). Bioevaluation showed that these quinazoline-based hydroxamic acids and N-hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). In term of cytotoxicity, several compounds, e.g. 4g, 4c, 4g-i, 6c, and 6h, displayed from 5- up to 10-fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat)...
April 18, 2018: Chemistry & Biodiversity
https://www.readbyqxmd.com/read/29660006/validation-of-post-operative-residual-contrast-enhancing-tumor-volume-as-an-independent-prognostic-factor-for-overall-survival-in-newly-diagnosed-glioblastoma
#10
Benjamin M Ellingson, Lauren E Abrey, Sarah J Nelson, Timothy J Kaufmann, Josep Garcia, Olivier Chinot, Frank Saran, Ryo Nishikawa, Roger Henriksson, Warren P Mason, Wolfgang Wick, Nicholas Butowski, Keith L Ligon, Elizabeth R Gerstner, Howard Colman, John de Groot, Susan Chang, Ingo Mellinghoff, Robert J Young, Brian M Alexander, Rivka Colen, Jennie W Taylor, Isabel Arrillaga-Romany, Arnav Mehta, Raymond Y Huang, Whitney B Pope, David Reardon, Tracy Batchelor, Michael Prados, Evanthia Galanis, Patrick Y Wen, Timothy F Cloughesy
Background: In the current study, we pooled imaging data in newly diagnosed GBM patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between post-operative residual enhancing tumor volume and overall survival (OS). Methods: Data from 1,511 newly diagnosed GBM patients from 5 data sources were included in the current study: 1) a single institution database from UCLA (N=398; Discovery); 2) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N=262 from 8 centers; Confirmation); 3) the chemoradiation placebo arm from an international phase III trial (AVAglio; N=394 from 120 locations in 23 countries; Validation); 4) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N=404 from 120 locations in 23 countries; Exploratory Set 1); and 5) an Alliance (N0874) Phase I/II trial of vorinostat plus chemoradiation (N=53; Exploratory Set 2)...
April 5, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/29658588/autophagy-inhibition-potentiates-saha%C3%A2-mediated-apoptosis-in-glioblastoma-cells-by-accumulation-of-damaged-mitochondria
#11
Kovooru Lohitesh, Heena Saini, Abhilasha Srivastava, Sudeshna Mukherjee, Aniruddha Roy, Rajdeep Chowdhury
Glioblastoma multiforme (GBM), often referred to as a grade IV astrocytoma, is the most invasive type of tumor arising from glial cells. The main treatment options for GBM include surgery, radiation and chemotherapy. However, these treatments tend to be only palliative rather than curative. Poor prognosis of GBM is due to its marked resistance to standard therapy. Currently, temozolomide (TMZ), an alkylating agent is used for treatment of GBM. However, GBM cells can repair TMZ‑induced DNA damage and therefore diminish the therapeutic efficacy of TMZ...
April 16, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29628874/saha-vorinostat-corrects-inhibitory-synaptic-deficits-caused-by-missense-epilepsy-mutations-to-the-gaba-a-receptor-%C3%AE-2-subunit
#12
Nela Durisic, Angelo Keramidas, Christine L Dixon, Joseph W Lynch
The GABAA receptor (GABAA R) α1 subunit A295D epilepsy mutation reduces the surface expression of α1A295D β2γ2 GABAA Rs via ER-associated protein degradation. Suberanilohydroxamic acid (SAHA, also known as Vorinostat) was recently shown to correct the misfolding of α1A295D subunits and thereby enhance the functional surface expression of α1A295D β2γ2 GABAA Rs. Here we investigated whether SAHA can also restore the surface expression of γ2 GABAA R subunits that incorporate epilepsy mutations (N40S, R43Q, P44S, R138G) known to reduce surface expression via ER-associated protein degradation...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29620153/histone-deacetylase-inhibitors-alter-the-expression-of-molecular-markers-in-breast-cancer-cells-via-micrornas
#13
Yehui Shi, Yongsheng Jia, Weipeng Zhao, Liyan Zhou, Xiaojuan Xie, Zhongsheng Tong
Histone deacetylase inhibitors (HDACis) are able to suppress breast cancer cells in vitro and in vivo by altering the expression of estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (Her2/neu). Since HDACis can alter the expression of various microRNAs (miRNAs/miRs), the present study aimed to examine the role of miRNAs in the effects of HDACis on breast cancer cells. We first examined the mRNA expression of ER, PR, and Her2/neu using RT-PCR and the protein levels of ER, PR, and Her2/neu using western blot analysis in MDA-MB-231 and BT474 cells, after trichostatin A (TSA) or vorinostat (SAHA) treatment...
April 3, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29603591/phase-i-study-of-vorinostat-in-combination-with-isotretinoin-in-patients-with-refractory-recurrent-neuroblastoma-a-new-approaches-to-neuroblastoma-therapy-nant-trial
#14
Navin Pinto, Steven G DuBois, Araz Marachelian, Scott J Diede, Agne Taraseviciute, Julia L Glade Bender, Denice Tsao-Wei, Susan G Groshen, Joel M Reid, Daphne A Haas-Kogan, C Patrick Reynolds, Min H Kang, Meredith S Irwin, Margaret E Macy, Judith G Villablanca, Katherine K Matthay, Julie R Park
BACKGROUND: Vorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD...
March 30, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29593039/il-15-stimulated-natural-killer-cells-clear-hiv-1-infected-cells-following-latency-reversal-ex-vivo
#15
Carolina Garrido, Maria Abad-Fernandez, Marina Tuyishime, Justin J Pollara, Guido Ferrari, Natalia Soriano-Sarabia, David M Margolis
Current efforts towards HIV eradication include approaches to augment immune recognition and elimination of persistently infected cells following latency reversal. Natural killer (NK) cells, the main effectors of the innate immune system, recognize and clear targets using different mechanisms than CD8+ T cells, offering an alternative or complementary approach for HIV clearance strategies. We assessed the impact of IL-15 treatment on NK cell function and the potential of stimulated NK cells to clear the HIV reservoir...
March 28, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29579058/comparative-oncology-approach-to-drug-repurposing-in-osteosarcoma
#16
Alejandro Parrales, Peter McDonald, Megan Ottomeyer, Anuradha Roy, Frank J Shoenen, Melinda Broward, Tyce Bruns, Douglas H Thamm, Scott J Weir, Kathleen A Neville, Tomoo Iwakuma, Joy M Fulbright
BACKGROUND: Osteosarcoma is an orphan disease for which little improvement in survival has been made since the late 1980s. New drug discovery for orphan diseases is limited by the cost and time it takes to develop new drugs. Repurposing already approved FDA-drugs can help overcome this limitation. Another limitation of cancer drug discovery is the lack of preclinical models that accurately recapitulate what occurs in humans. For OS using dogs as a model can minimize this limitation as OS in canines develops spontaneously, is locally invasive and metastasizes to the lungs as it does in humans...
2018: PloS One
https://www.readbyqxmd.com/read/29567781/a-novel-regimen-for-relapsed-refractory-adult-acute-myeloid-leukemia-using-a-kmt2a-partial-tandem-duplication-targeted-therapy-results-of-phase-1-study-nci-8485
#17
Alice S Mims, Anjali Mishra, Shelley Orwick, James Blachly, Rebecca B Klisovic, Ramiro Garzon, Alison R Walker, Steven M Devine, Katherine J Walsh, Sumithira Vasu, Susan Whitman, Guido Marcucci, Daniel Jones, Nyla A Heerema, Gerard Lozanski, Michael A Caligiuri, Clara D Bloomfield, John C Byrd, Richard Piekarz, Michael R Grever, William Blum
KMT2A partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemo-response...
March 22, 2018: Haematologica
https://www.readbyqxmd.com/read/29551127/advances-and-challenges-of-hdac-inhibitors-in-cancer-therapeutics
#18
Jesse J McClure, Xiaoyang Li, C James Chou
Since the identification and cloning of human histone deacetylases (HDACs) and the rapid approval of vorinostat (Zolinza®) for the treatment of cutaneous T-cell lymphoma, the field of HDAC biology has met many initial successes. However, many challenges remain due to the complexity involved in the lysine posttranslational modifications, epigenetic transcription regulation, and nonepigenetic cellular signaling cascades. In this chapter, we will: review the discovery of the first HDAC inhibitor and present discussion regarding the future of next-generation HDAC inhibitors, give an overview of different classes of HDACs and their differences in lysine deacylation activity, discuss different classes of HDAC inhibitors and their HDAC isozyme preferences, and review HDAC inhibitors' preclinical studies, their clinical trials, their pharmacokinetic challenges, and future direction...
2018: Advances in Cancer Research
https://www.readbyqxmd.com/read/29534238/targeting-epigenetic-dna-and-histone-modifications-to-treat-kidney-disease
#19
Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Olga Ruiz-Andres, Jonay Poveda, Maria Dolores Sanchez-Niño, Lara Valiño-Rivas, Marta Ruiz-Ortega, Alberto Ortiz, Ana Belén Sanz
Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease...
March 9, 2018: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/29513522/light-trigerred-cellular-epigenetic-molecule-release-to-reverse-tumor-multidrug-resistance
#20
Leilei Shi, Li Xu, Qinghua Guan, Xin Jin, Jiapei Yang, Xinyuan Zhu
Owing to the high spatial and temporal resolution of light, light-related biotechnologies, for example, optogenetics, has wide ranging applications in neuroscience to control a subject's behavior. Applying light to control tumors' genetic behavior directly was still a challenge so far. Herein, we put forward a strategy of chemical optoepigenomics, in which an epigenetic regulator (vorinostat) and paclitaxel (PTX) were conjugated onto a light-sensitive chemical molecule. The activity of vorinostat could be precisely controlled by the light, which could minimize the off-target effect...
April 18, 2018: Bioconjugate Chemistry
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