scholarly journals Histone Deacetylase (HDAC) Inhibitors for the Treatment of Schistosomiasis

2022 ◽  
Vol 15 (1) ◽  
pp. 80
Author(s):  
Ehab Ghazy ◽  
Mohamed Abdelsalam ◽  
Dina Robaa ◽  
Raymond J. Pierce ◽  
Wolfgang Sippl
Keyword(s):  
Life Cycle ◽  
Histone Deacetylase ◽  
Control Strategy ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Hdac Inhibitors ◽  
Parasitic Disease ◽  
Mass Treatment ◽  
Epigenetic Mechanisms ◽  
Histone Deacetylase 8

Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. Schistosomes display morphologically distinct stages during their life cycle and the transformations between stages are controlled by epigenetic mechanisms. The targeting of epigenetic actors might therefore represent the parasites’ Achilles’ heel. Specifically, histone deacetylases have been recently characterized as drug targets for the treatment of schistosomiasis. This review focuses on the recent development of inhibitors for schistosome histone deacetylases. In particular, advances in the development of inhibitors of Schistosoma mansoni histone deacetylase 8 have indicated that targeting this enzyme is a promising approach for the treatment of this infection.

scholarly journals Cystathionine γ-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6

2017 ◽  
Vol 312 (4) ◽  
pp. H711-H720 ◽  
Author(s):  
Thorsten M. Leucker ◽  
Yohei Nomura ◽  
Jae Hyung Kim ◽  
Anil Bhatta ◽  
Victor Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Histone Deacetylase ◽  
Vascular Endothelium ◽  
High Fat Diet ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Oxidized Ldl ◽  
Hdac Inhibitors ◽  
Histone Deacetylase 6 ◽  
High Fat

Endothelial cystathionine γ-lyase (CSEγ) contributes to cardiovascular homeostasis, mainly through production of H2S. However, the molecular mechanisms that control CSEγ gene expression in the endothelium during cardiovascular diseases are unclear. The aim of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial CSEγ. Reduced CSEγ mRNA expression and protein abundance were observed in human aortic endothelial cells (HAEC) exposed to oxidized LDL (OxLDL) and in aortas from atherogenic apolipoprotein E knockout (ApoE−/−) mice fed a high-fat diet compared with controls. Intact murine aortic rings exposed to OxLDL (50 μg/ml) for 24 h exhibited impaired endothelium-dependent vasorelaxation that was blocked by CSEγ overexpression or the H2S donor NaHS. CSEγ expression was upregulated by pan-HDAC inhibitors and by class II-specific HDAC inhibitors, but not by other class-specific inhibitors. The HDAC6 selective inhibitor tubacin and HDAC6-specific siRNA increased CSEγ expression and blocked OxLDL-mediated reductions in endothelial CSEγ expression and CSEγ promoter activity, indicating that HDAC6 is a specific regulator of CSEγ expression. Consistent with this finding, HDAC6 mRNA, protein expression, and activity were upregulated in OxLDL-exposed HAEC, but not in human aortic smooth muscle cells. HDAC6 protein levels in aortas from high-fat diet-fed ApoE−/− mice were comparable to those in controls, whereas HDAC6 activity was robustly upregulated. Together, our findings indicate that HDAC6 is upregulated by atherogenic stimuli via posttranslational modifications and is a critical regulator of CSEγ expression in vascular endothelium. Inhibition of HDAC6 activity may improve endothelial function and prevent or reverse the development of atherosclerosis. NEW & NOTEWORTHY Oxidative injury to endothelial cells by oxidized LDL reduced cystathionine γ-lyase (CSEγ) expression and H2S production, leading to endothelial dysfunction, which was prevented by histone deacetylase 6 (HDAC6) inhibition. Our data suggest HDAC6 as a novel therapeutic target to prevent the development of atherosclerosis.

Recent Studies on HDAC Inhibitors Acting against Prostate Cancer

2020 ◽  
Vol 16 (1) ◽  
pp. 74-89 ◽  
Author(s):  
Basheerulla Shaik ◽  
Tabassum Zafar ◽  
Satya P. Gupta
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Hdac Inhibitors ◽  
Epigenetic Mechanisms ◽  
Anticancer Efficacy ◽  
Cycle Arrest

Prostate cancer is one of the prominent death cause in males with alarming rates of inclusion of new cases each year. There are many new classes of anti-tumor agents already investigated that modulate the epigenetic or non-epigenetic mechanisms such as cell cycle arrest, apoptosis, cell death within cancer cells. Histone deacetylase (HDAC) inhibitors are one of them. In recent times, the use of HADC inhibitors are approved as a clinical molecule to treat a group of malignancies. Vorinostat and depsipeptide are two new HDAC inhibitors that are approved by the Food and Drug Administration. The present review is an effort to summarize the recent findings related to HDAC inhibitors against prostate cancer along with their molecular mechanism and biological mode of actions behind the anticancer efficacy.

scholarly journals Kinetic Characterization of Human Histone Deacetylase 8 With Medium-Chain Fatty Acyl Lysine

2021 ◽  
Vol 14 ◽  
pp. 251686572110656
Author(s):  
Harrison Yoo ◽  
Gregory A Polsinelli
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Decanoic Acid ◽  
Fatty Acyl ◽  
Peptide Substrate ◽  
Medium Chain ◽  
Histone Deacetylase 8 ◽  
Lysine Residues

Histone deacetylases (HDACs) catalyze the removal of Ɛ-acetyl-lysine residues of histones via hydrolysis. Removal of acetyl groups results in condensation of chromatin structure and alteration of gene expression by repression. HDACs are considered targets for the treatment of cancer due to their role in regulating transcription. HDAC8 inhibition may be an important anti-proliferative factor for histone deacetylase inhibitors on cancer cells and may give rise to the progression of apoptosis. HDAC8 activity was analyzed with various peptides where the target lysine is modified with medium-chain fatty acyl group. Kinetic data were determined for each p53 peptide substrate. The results suggest that there was HDAC8 deacetylase activity on peptide substrate as well as deacylase activity with acylated peptide substrate variants. HDAC8 inhibition by hexanoic and decanoic acid was also examined. The Ki for hexanoic and decanoic acid were determined to be 2.35 ± 0.341 and 4.48 ± 0.221 mM, respectively.

scholarly journals Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated

2018 ◽  
Author(s):  
Magalie Géraldy ◽  
Michael Morgen ◽  
Peter Sehr ◽  
Raphael R. Steimbach ◽  
Johannes Ridinger ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Drug Targets ◽  
Neuroblastoma Cell ◽  
Chemotherapy Resistance ◽  
Hdac Inhibitors ◽  
Selective Inhibition ◽  
Neuroblastoma Cell Line ◽  
Autophagic Flux ◽  
Ligand Displacement ◽  
Homology Models

The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as clinical drug targets. The isozyme HDAC10 contributes to chemotherapy resistance via inhibition of autophagic flux and has recently been described to be a polyamine deacetylase, but no studies directed toward selective HDAC10 inhibitors have been published. Herein, we disclose that the use of two complementary ligand-displacement assays has revealed unexpectedly potent HDAC10 binding of tubastatin A, which has been previously described as a highly selective HDAC6 inhibitor. We synthesized a targeted selection of tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10, but not HDAC6, binding. Only potent HDAC10 binders mimicked HDAC10 knockdown by causing dose-dependent accumulation of acidic vesicles in the BE(2)-C neuroblastoma cell line. Docking of inhibitors into human HDAC10 homology models indicated that a hydrogen-bond between a basic cap group nitrogen and the HDAC10 gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, the presented assays and homology models provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the tubastatin A scaffold.<br>

scholarly journals Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated

2018 ◽  
Author(s):  
Magalie Géraldy ◽  
Michael Morgen ◽  
Peter Sehr ◽  
Raphael R. Steimbach ◽  
Johannes Ridinger ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Drug Targets ◽  
Neuroblastoma Cell ◽  
Chemotherapy Resistance ◽  
Hdac Inhibitors ◽  
Selective Inhibition ◽  
Neuroblastoma Cell Line ◽  
Autophagic Flux ◽  
Ligand Displacement ◽  
Homology Models

The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as clinical drug targets. The isozyme HDAC10 contributes to chemotherapy resistance via inhibition of autophagic flux and has recently been described to be a polyamine deacetylase, but no studies directed toward selective HDAC10 inhibitors have been published. Herein, we disclose that the use of two complementary ligand-displacement assays has revealed unexpectedly potent HDAC10 binding of tubastatin A, which has been previously described as a highly selective HDAC6 inhibitor. We synthesized a targeted selection of tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10, but not HDAC6, binding. Only potent HDAC10 binders mimicked HDAC10 knockdown by causing dose-dependent accumulation of acidic vesicles in the BE(2)-C neuroblastoma cell line. Docking of inhibitors into human HDAC10 homology models indicated that a hydrogen-bond between a basic cap group nitrogen and the HDAC10 gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, the presented assays and homology models provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the tubastatin A scaffold.<br>

scholarly journals An active site tyrosine residue is essential for amidohydrolase but not for esterase activity of a class 2 histone deacetylase-like bacterial enzyme

2007 ◽  
Vol 401 (3) ◽  
pp. 659-665 ◽  
Author(s):  
Kristin Moreth ◽  
Daniel Riester ◽  
Christian Hildmann ◽  
René Hempel ◽  
Dennis Wegener ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Active Site ◽  
Esterase Activity ◽  
Histone Deacetylases ◽  
Biological Activities ◽  
Hdac Inhibitors ◽  
Porcine Liver ◽  
Drug Candidates ◽  
Core Histones ◽  
Ic50 Values

HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells acting through deacetylation of ϵ-acetyl-lysine residues within the N-terminal tail of core histones. In addition, both eukaryotic HDACs as well as their bacterial counterparts were reported to also act on non-histone targets. However, we are still far from a comprehensive understanding of the biological activities of this ancient class of enzymes. In the present paper, we studied in more detail the esterase activity of HDACs, focussing on the HDAH (histone deacetylase-like amidohydrolase) from Bordetella/Alcaligenes strain FB188. This enzyme was classified as a class 2 HDAC based on sequence comparison as well as functional data. Using chromogenic and fluorogenic ester substrates we show that HDACs such as FB188 HDAH indeed have esterase activity that is comparable with those of known esterases. Similar results were obtained for human HDAC1, 3 and 8. Standard HDAC inhibitors were able to block both activities with similar IC50 values. Interestingly, HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA) also showed inhibitory activity against porcine liver esterase and Pseudomonas fluorescens lipase. The esterase and the amidohydrolase activity of FB188 HDAH both appear to have the same substrate specificity concerning the acyl moiety. Interestingly, a Y312F mutation in the active site of HDAH obstructed amidohydrolase activity but significantly improved esterase activity, indicating subtle differences in the mechanism of both catalytic activities. Our results suggest that, in principle, HDACs may have other biological roles besides acting as protein deacetylases. Furthermore, data on HDAC inhibitors affecting known esterases indicate that these molecules, which are currently among the most promising drug candidates in cancer therapy, may have a broader target profile requiring further exploration.

scholarly journals Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway

2019 ◽  
Vol 20 (5) ◽  
pp. 1162 ◽  
Author(s):  
Fu-Shun Hsu ◽  
June-Tai Wu ◽  
Jing-Yi Lin ◽  
Shao-Ping Yang ◽  
Kuan-Lin Kuo ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Erk Pathway ◽  
Antitumor Effects ◽  
Nude Mouse Model ◽  
Synergistic Cytotoxicity ◽  
Histone Deacetylase Inhibitor Trichostatin

Trichostatin A (TSA), an antifungal antibiotic derived from Streptomyces, inhibits mammalian histone deacetylases, and especially, selectively inhibits class I and II histone deacetylase (HDAC) families of enzymes. TSA reportedly elicits an antiproliferative response in multifarious tumors. This study investigated the antitumor effects of TSA alone and in combination with paclitaxel when applied to two high-grade urothelial carcinoma (UC) cell lines (BFTC-905 and BFTC-909). Fluorescence-activated cell sorting, flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay were used to assess TSA’s cytotoxicity and effects on apoptosis induction. TSA induced synergistic cytotoxicity, when combined with paclitaxel (combination index < 1), resulted in concomitant suppression of paclitaxel-induced activation of phospho-extracellular signal-regulated kinase (ERK) 1/2. A xenograft nude mouse model confirmed that TSA enhances the antitumor effects of paclitaxel. These findings demonstrate that the administration of TSA in combination with paclitaxel elicits a synergistic cytotoxic response. The results of this study indicate that the chemoresistance of UC could be circumvented by combining HDAC inhibitors to target the ERK pathway.

scholarly journals A miniaturized readout strategy for endogenous histone deacetylase activity

2015 ◽  
Vol 11 (7) ◽  
pp. 1820-1823 ◽  
Author(s):  
Jan Oliver Jost ◽  
Alfred Hanswillemenke ◽  
Dirk Schwarzer
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Important Drug

Histone deacetylases are important drug targets, which are difficult to characterize due to their poor accessibility.

scholarly journals Next-generation of selective histone deacetylase inhibitors

RSC Advances ◽  
2019 ◽  
Vol 9 (34) ◽  
pp. 19571-19583 ◽  
Author(s):  
Feifei Yang ◽  
Na Zhao ◽  
Di Ge ◽  
Yihua Chen
Keyword(s):  
Cancer Treatment ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Histone Deacetylase Inhibitors ◽  
Next Generation ◽  
Epigenetic Drug

Histone deacetylases (HDACs) are clinically validated epigenetic drug targets for cancer treatment.

Histone deacetylase inhibitors suppress IFNα-induced up-regulation of promyelocytic leukemia protein

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1373-1380 ◽  
Author(s):  
Jana Vlasáková ◽  
Zora Nováková ◽  
Lenka Rossmeislová ◽  
Michal Kahle ◽  
Pavel Hozák ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Eukaryotic Cell ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Interferon Α

Abstract Promyelocytic leukemia nuclear bodies (PML NBs), the structural domains of the eukaryotic cell nucleus, play a role in cancer and apoptosis, and their involvement in antiviral mechanisms mediated by interferons (IFNs) is proposed. IFNs dramatically increase the transcription of the PML gene. In this study, we have shown that the response of 2 structural PML NB components, PML and Sp100, to interferon-α (IFNα) was suppressed in cells simultaneously treated with histone deacetylase (HDAC) inhibitors (trichostatin A, sodium butyrate, MS-275, SAHA, and valproic acid). Trichostatin A (TSA) blocked the increase of PML NB number and suppressed up-regulation of PML mRNA and protein levels in several human cell lines and in normal diploid skin fibroblasts. Moreover, IFNα induction of IRF-1 was also inhibited by TSA, although incompletely. Analysis of cellular fractions did not show any defects in cytoplasmic-nuclear transport of STAT2, a component of transcription factor ISGF3 responsible for IFNα/β-dependent gene transcription. Moreover, chromatin immunoprecipitation showed that after IFNα stimulation STAT2 binds to ISRE element of PML promoter even in the presence of TSA and thus excluded STAT2-dependent mechanism of TSA effect. These results indicate that the action of histone deacetylases is necessary for the full transcriptional activation of IFNα-stimulated genes.

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