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Berlin Brandenburg

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  • Histone Deacetylase Inhibitors
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  • 1
    Language: English
    In: Journal of medicinal chemistry, 25 February 2016, Vol.59(4), pp.1545-55
    Description: Histone deacetylase 6 (HDAC6) catalyzes the removal of an acetyl group from lysine residues of several non-histone proteins. Here we report the preparation of thiazole-, oxazole-, and oxadiazole-containing biarylhydroxamic acids by a short synthetic procedure. We identified them as selective HDAC6 inhibitors by investigating the inhibition of recombinant HDAC enzymes and the protein acetylation in cells by Western blotting (tubulin vs histone acetylation). The most active compounds exhibited nanomolar potency and high selectivity for HDAC6. For example, an oxazole hydroxamate inhibits HDAC6 with an IC50 of 59 nM and has a selectivity index of 〉200 against HDAC1 and HDAC8. This is the first report showing that the nature of a heterocycle directly connected to a zinc binding group (ZBG) can be used to modulate subtype selectivity and potency for HDAC6 inhibitors to such an extent. We rationalize the high potency and selectivity of the oxazoles by molecular modeling and docking.
    Keywords: Histone Deacetylase Inhibitors -- Chemistry ; Histone Deacetylases -- Metabolism ; Hydroxamic Acids -- Chemistry ; Oxazoles -- Chemistry
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 2
    Language: English
    In: International Journal of Cancer, 01 May 2013, Vol.132(9), pp.2200-2208
    Description: Inhibition of histone deacetylase (HDAC) activity as stand‐alone or combination therapy represents a promising therapeutic approach in oncology. The pan‐ or class I HDAC inhibitors (HDACi) currently approved or in clinical studies for oncology give rise to dose‐limiting toxicities, presumably because of the inhibition of several HDACs. This could potentially be overcome by selective blockade of single HDAC family members. Here we report that HDAC11, the most recently identified zinc‐dependent HDAC, is overexpressed in several carcinomas as compared to corresponding healthy tissues. HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in HCT‐116 colon, PC‐3 prostate, MCF‐7 breast and SK‐OV‐3 ovarian cancer cell lines. The antitumoral effect induced can be mimicked by enforced expression of a catalytically impaired HDAC11 variant, suggesting that inhibition of the enzymatic activity of HDAC11 by small molecules could trigger the desired phenotypic changes. HDAC11 depletion in normal cells causes no changes in metabolic activity and viability, strongly suggesting that tumor‐selective effects can be achieved. Altogether, our data show that HDAC11 plays a critical role in cancer cell survival and may represent a novel drug target in oncology. What's new? Histone deacetylase (HDAC) enzymes influence the regulation of numerous cellular processes, and their inhibition by small molecules has been shown to provide benefits against multiple cancer types. Here, HDAC11, a recently identified member of the HDAC family, was found to play an important role in the control of proliferation and survival pathways in several carcinoma cell lines. The high incidence of the tumors represented suggests that HDAC11 could be a valuable drug target in oncology.
    Keywords: Chromatin Modulation ; Targeted Therapy ; Histone Deacetylase ; Colon Cancer ; Prostate Cancer
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 09 July 2013, Vol.110(28), pp.E2592-601
    Description: Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.
    Keywords: Hdac Inhibitor ; Childhood Tumors ; Drug Resistance ; Autophagy -- Physiology ; Cell Survival -- Physiology ; Histone Deacetylases -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    Language: English
    In: CNS oncology, July 2013, Vol.2(4), pp.359-76
    Description: Histone deacetylase inhibitors (HDACis) have fascinated researchers in almost all fields of oncology for many years owing to their pleiotropic effects on nearly every aspect of cancer biology. Since the approval of the first HDACi vorinostat for the treatment of cutaneous T-cell leukemia in 2006, more than a hundred clinical trials have been initiated with a HDACi as a single agent or in combination therapy. Although a number of epigenetic and nonepigenetic molecular mechanisms of action have been proposed, biomarkers for response prediction and patient selection are still lacking. One of the inherent problems in the field of HDACis is their 'reverse' history of drug development: these compounds reached clinical application at an early stage, before the biology of their targets, HDAC1-11, was sufficiently understood. This review summarizes the current knowledge on the human family of HDACs as drug targets in pediatric and adult brain tumors, the efficacy and molecular action of HDACis in preclinical models, as well as the current status of the clinical development of these compounds in the field of neuro-oncology.
    Keywords: Brain Neoplasms -- Drug Therapy ; Histone Deacetylase Inhibitors -- Therapeutic Use ; Histone Deacetylases -- Metabolism
    ISSN: 20450907
    E-ISSN: 2045-0915
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  • 5
    Language: English
    In: NUCLEIC ACIDS RESEARCH, 2013
    Description: MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function.
    Keywords: Biology And Life Sciences ; Cell-Line ; Down-Regulation ; Microrna Expression ; Colorectal-Cancer ; Apoptosis ; Microarray ; Carcinoma ; Family ; Differentiation ; Histone Deacetylase Inhibitors
    ISSN: 0305-1048
    E-ISSN: 13624962
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  • 6
    Language: English
    In: International Journal of Radiation Oncology, Biology, Physics, 2010, Vol.78(1), pp.237-245
    Description: Histone deacetylase inhibitors (HDACIs) can enhance the sensitivity of cells to photon radiation treatment (XRT) by altering numerous molecular pathways. We investigated the effect of pan-HDACIs such as suberoylanilide hydroxamic acid (SAHA) on radiation response in two osteosarcoma (OS) and two rhabdomyosarcoma (RMS) cell lines. Clonogenic survival, cell cycle analysis, and apoptosis were examined in OS (KHOS-24OS, SAOS2) and RMS (A-204, RD) cell lines treated with HDACI and HDACI plus XRT, respectively. Protein expression was investigated via immunoblot analysis, and cell cycle analysis and measurement of apoptosis were performed using flow cytometry. SAHA induced an inhibition of cell proliferation and clonogenic survival in OS and RMS cell lines and led to a significant radiosensitization of all tumor cell lines. Other HDACI such as M344 and valproate showed similar effects as investigated in one OS cell line. Furthermore, SAHA significantly increased radiation-induced apoptosis in the OS cell lines, whereas in the RMS cell lines radiation-induced apoptosis was insignificant with and without SAHA. In all investigated sarcoma cell lines, SAHA attenuated radiation-induced DNA repair protein expression (Rad51, Ku80). Our results show that HDACIs enhance radiation action in OS and RMS cell lines. Inhibition of DNA repair, as well as increased apoptosis induction after exposure to HDACIs, can be mechanisms of radiosensitization by HDACIs.
    Keywords: Sarcoma ; Histone Deacetylase Inhibition ; Suberoylanilide Hydroxamic Acid (Saha) ; Radiosensitization ; Medicine
    ISSN: 0360-3016
    E-ISSN: 1879-355X
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  • 7
    Language: English
    In: Autophagy, 05 December 2013, Vol.9(12), pp.2163-2165
    Description: Neuroblastoma is the most common extracranial solid tumor in childhood. Despite intense multimodal therapy and many improvements through basic scientific and clinical research, the successful response of advanced-stage patients to chemotherapy remains poor. Autophagy is a cytoprotective mechanism...
    Keywords: Hdac10 ; Neuroblastoma ; Drug Resistance ; Hdac-Inhibitor ; Lysosome ; Macroautophagy ; Biology
    ISSN: 1554-8627
    E-ISSN: 1554-8635
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  • 8
    Language: English
    In: Cancer Letters, 2009, Vol.277(1), pp.8-21
    Description: Histone deacetylases comprise a family of 18 genes, which are grouped into classes I–IV based on their homology to their respective yeast orthologues. Classes I, II, and IV consist of 11 family members, which are referred to as “classical” HDACs, whereas the 7 class III members are called sirtuins. Classical HDACs are a promising novel class of anti-cancer drug targets. First HDAC inhibitors have been evaluated in clinical trials and show activity against several cancer diseases. However, these compounds act unselectively against several or all 11 HDAC family members. As a consequence, clinical phase I trials document a wide range of side effects. Therefore, the current challenge in the field is to define the cancer relevant HDAC family member(s) in a given tumor type and to design selective inhibitors, which target cancer cells but leave out normal cells. Knockout of single HDAC family members in mice produces a variety of phenotypes ranging from early embryonic death to viable animals with only discrete alterations, indicating that potential side effects of HDAC inhibitors depend on the selectivity of the compounds. Recently, several studies have shown that certain HDAC family members are aberrantly expressed in several tumors and have non-redundant function in controlling hallmarks of cancer cells. The aim of this review is to discuss individual HDAC family members as drug targets in cancer taking into consideration their function under physiological conditions and their oncogenic potential in malignant disease.
    Keywords: Histone Deacetylase ; Hdac ; Hdac Inhibitor ; Cancer ; Development ; Therapy ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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  • 9
    Language: English
    In: Journal of Chromatography B, 01 August 2014, Vol.964, pp.212-221
    Description: Vorinostat (suberoylanilide hydroxamic acid) is the first approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma after progressive disease following two systemic therapies. Intracellular access of vorinostat is essential to exert its epigenetic effects. Therefore, we studied the relationship between vorinostat extracellular (plasma) and intracellular (peripheral blood mononuclear cells, PBMCs) concentration and assessed its concentration-effect relationship by HDAC activity testing. Assays were developed and validated for the low nanomolar quantification of vorinostat and two inactive metabolites in human plasma and PBMCs. For the vorinostat extraction from plasma and PBMCs solid-phase extraction and liquid–liquid extraction methods were applied. Extraction recoveries ranged from 88.6% to 114.4% for all analytes and extraction methods. Extracts were chromatographed on a Phenomenex Luna column isocratically (plasma) or by gradient (PBMCs) consisting of acidic ammonium acetate, acetonitrile, and methanol. The analytes were quantified using deuterated internal standards and positive electrospray tandem mass spectrometry (multiple reaction monitoring) with lower limits of quantification of 11.0 ng/mL (plasma) and 0.1 ng/3 × 10 cells (PBMCs). The calibrated ranges were linear for vorinostat in plasma 11.0–1100 (11,000) ng/mL (metabolites) and PBMCs 0.1–10.0 ng/3 × 10 cells with correlation coefficients 〉0.99, an overall accuracy varying between −6.7% and +3.8% in plasma, −8.1% and −1.5% in PBMCs, and an overall precision ranging from 3.2% to 6.1% in plasma and 0.8% to 4.0% in PBMCs (SD batch-to-batch). The application to blood samples from healthy volunteers incubated with vorinostat revealed accumulation of vorinostat in PBMCs, effective intracellular HDAC inhibition at therapeutic vorinostat concentrations and a direct vorinostat concentration dependency to HDAC inhibition.
    Keywords: Vorinostat ; Tandem Mass Spectrometry ; Plasma ; Peripheral Blood Mononuclear Cells ; Histone Deacetylase Activity ; Anatomy & Physiology
    ISSN: 1570-0232
    E-ISSN: 1873-376X
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  • 10
    In: Pediatric Blood & Cancer, September 2016, Vol.63(9), pp.1677-1679
    Description: Children with Down syndrome are at high risk to develop myeloid leukemia (ML‐DS). Despite their excellent prognosis, children with ML‐DS particularly suffer from severe therapy‐related toxicities and for relapsed ML‐DS the cure rates are very poor. Here we report the clinical course of one child with ML‐DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML‐DS.
    Keywords: Aml ; Down Syndrome ; Hdac ; Hdaci ; Histone Deacetylase Inhibitor ; Ml‐Ds ; Vorinostat
    ISSN: 1545-5009
    E-ISSN: 1545-5017
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