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Experimental & Molecular Medicine Sep 2022Increased focus has been placed on the role of histone deacetylase inhibitors as crucial players in subarachnoid hemorrhage (SAH) progression. Therefore, this study was...
Increased focus has been placed on the role of histone deacetylase inhibitors as crucial players in subarachnoid hemorrhage (SAH) progression. Therefore, this study was designed to expand the understanding of SAH by exploring the downstream mechanism of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in SAH. The expression of TDP-43 in patients with SAH and rat models of SAH was measured. Then, western blot analysis, immunofluorescence staining, and transmission electron microscope were used to investigate the in vitro effect of TDP-43 on a neuronal cell model of SAH established by oxyhemoglobin treatment. Immunofluorescence staining and coimmunoprecipitation assays were conducted to explore the relationship among histone deacetylase 1 (HDAC1), heat shock protein 70 (HSP70), and TDP-43. Furthermore, the in vivo effect of HDAC1 on SAH was investigated in rat models of SAH established by endovascular perforation. High expression of TDP-43 in the cerebrospinal fluid of patients with SAH and brain tissues of rat models of SAH was observed, and TDP-43 accumulation in the cytoplasm and the formation of inclusion bodies were responsible for axonal damage, abnormal nuclear membrane morphology, and apoptosis in neurons. TDP-43 degradation was promoted by the HDAC1 inhibitor SAHA via the acetylation of HSP70, alleviating SAH, and this effect was verified in vivo in rat models. In conclusion, SAHA relieved axonal damage and neurological dysfunction after SAH via the HSP70 acetylation-induced degradation of TDP-43, highlighting a novel therapeutic target for SAH.
Topics: Animals; Apoptosis; DNA-Binding Proteins; HSP70 Heat-Shock Proteins; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Hydroxamic Acids; Oxyhemoglobins; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Vorinostat
PubMed: 35501375
DOI: 10.1038/s12276-022-00761-9 -
JCI Insight Nov 2023Histone deacetylase (HDAC) inhibitors have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their...
Histone deacetylase (HDAC) inhibitors have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDAC inhibitors have failed to provide substantial clinical benefit to patients with glioblastoma (GBM) to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. Although no isoform-specific HDAC inhibitors are currently available, the second-generation hydroxamic acid-based HDAC inhibitor quisinostat possesses subnanomolar specificity for class I HDAC isoforms, particularly HDAC1 and HDAC2. It has been shown that HDAC1 is the essential HDAC in GBM. This study analyzed the neuropharmacokinetic, pharmacodynamic, and radiation-sensitizing properties of quisinostat in preclinical models of GBM. It was found that quisinostat is a well-tolerated and brain-penetrant molecule that extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.
Topics: Adult; Humans; Child; Histone Deacetylase Inhibitors; Glioblastoma; Hydroxamic Acids; Histone Deacetylases; Brain Neoplasms; Protein Isoforms; Brain
PubMed: 37991020
DOI: 10.1172/jci.insight.167081 -
Nature Communications Jan 2021Histones control gene expression by regulating chromatin structure and function. The posttranslational modifications (PTMs) on the side chains of histones form the...
Histones control gene expression by regulating chromatin structure and function. The posttranslational modifications (PTMs) on the side chains of histones form the epigenetic landscape, which is tightly controlled by epigenetic modulator enzymes and further recognized by so-called reader domains. Histone microarrays have been widely applied to investigate histone-reader interactions, but not the transient interactions of Zn-dependent histone deacetylase (HDAC) eraser enzymes. Here, we synthesize hydroxamic acid-modified histone peptides and use them in femtomolar microarrays for the direct capture and detection of the four class I HDAC isozymes. Follow-up functional assays in solution provide insights into their suitability to discover HDAC substrates and inhibitors with nanomolar potency and activity in cellular assays. We conclude that similar hydroxamic acid-modified histone peptide microarrays and libraries could find broad application to identify class I HDAC isozyme-specific substrates and facilitate the development of isozyme-selective HDAC inhibitors and probes.
Topics: Amino Acid Sequence; HEK293 Cells; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Isoenzymes; Microarray Analysis; Peptides; Protein Processing, Post-Translational; Zinc
PubMed: 33397936
DOI: 10.1038/s41467-020-20250-9 -
Pharmacogenomics Nov 2016The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase... (Review)
Review
The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping.
Topics: Depsipeptides; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Panobinostat; Pharmacogenetics; Sulfonamides; Valproic Acid; Vorinostat
PubMed: 27767376
DOI: 10.2217/pgs-2016-0113 -
Journal of Enzyme Inhibition and... Dec 2018Zinc binding groups (ZBGs) play a crucial role in targeting histone deacetylase inhibitors (HDACIs) to the active site of histone deacetylases (HDACs), thus determining... (Review)
Review
Zinc binding groups (ZBGs) play a crucial role in targeting histone deacetylase inhibitors (HDACIs) to the active site of histone deacetylases (HDACs), thus determining the potency of HDACIs. Due to the high affinity to the zinc ion, hydroxamic acid is the most commonly used ZBG in the structure of HDACs. An alternative ZBG is benzamide group, which features excellent inhibitory selectivity for class I HDACs. Various ZBGs have been designed and tested to improve the activity and selectivity of HDACIs, and to overcome the pharmacokinetic limitations of current HDACIs. Herein, different kinds of ZBGs are reviewed and their features have been discussed for further design of HDACIs.
Topics: Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Structure-Activity Relationship; Zinc
PubMed: 29616828
DOI: 10.1080/14756366.2017.1417274 -
Cancer Prevention Research... Jun 2023Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor with anticancer effects via epigenetic and non-epigenetic mechanisms. The role of SAHA...
UNLABELLED
Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor with anticancer effects via epigenetic and non-epigenetic mechanisms. The role of SAHA in metabolic rewiring and epigenomic reprogramming to inhibit pro-tumorigenic cascades in lung cancer remains unknown. In this study, we aimed to investigate the regulation of mitochondrial metabolism, DNA methylome reprogramming, and transcriptomic gene expression by SAHA in lipopolysaccharide (LPS)-induced inflammatory model of lung epithelial BEAS-2B cells. LC/MS was used for metabolomic analysis, while next-generation sequencing was done to study epigenetic changes. The metabolomic study reveals that SAHA treatment significantly regulated methionine, glutathione, and nicotinamide metabolism with alteration of the metabolite levels of methionine, S-adenosylmethionine, S-adenosylhomocysteine, glutathione, nicotinamide, 1-methylnicotinamide, and nicotinamide adenine dinucleotide in BEAS-2B cells. Epigenomic CpG methyl-seq shows SAHA revoked a list of differentially methylated regions in the promoter region of the genes, such as HDAC11, miR4509-1, and miR3191. Transcriptomic RNA sequencing (RNA-seq) reveals SAHA abrogated LPS-induced differentially expressed genes encoding proinflammatory cytokines, including interleukin 1α (IL1α), IL1β, IL2, IL6, IL24, and IL32. Integrative analysis of DNA methylome-RNA transcriptome displays a list of genes, of which CpG methylation correlated with changes in gene expression. qPCR validation of transcriptomic RNA-seq data shows that SAHA treatment significantly reduced the LPS-induced mRNA levels of IL1β, IL6, DNA methyltransferase 1 (DNMT1), and DNMT3A in BEAS-2B cells. Altogether, SAHA treatment alters the mitochondrial metabolism, epigenetic CpG methylation, and transcriptomic gene expression to inhibit LPS-induced inflammatory responses in lung epithelial cells, which may provide novel molecular targets to inhibit the inflammation component of lung carcinogenesis.
PREVENTION RELEVANCE
Inflammation increases the risk of lung cancer and blocking inflammation could reduce the incidence of lung cancer. Herein, we demonstrate that histone deacetylase inhibitor suberoylanilide hydroxamic acid regulates metabolic rewiring and epigenetic reprogramming to attenuate lipopolysaccharide-driven inflammation in lung epithelial cells.
Topics: Humans; Vorinostat; Lipopolysaccharides; Interleukin-6; Transcriptome; Hydroxamic Acids; Histone Deacetylase Inhibitors; Lung; Inflammation; DNA; Lung Neoplasms; Epithelial Cells; Glutathione; Methionine
PubMed: 36867722
DOI: 10.1158/1940-6207.CAPR-22-0384 -
Journal of Enzyme Inhibition and... Dec 2020Oxazolidinone hydroxamic acid derivatives were synthesised and evaluated for inhibitory activity against leukotriene (LT) biosynthesis in three cell-based test systems...
Oxazolidinone hydroxamic acid derivatives were synthesised and evaluated for inhibitory activity against leukotriene (LT) biosynthesis in three cell-based test systems and on direct inhibition of recombinant human 5-lipoxygenase (5-LO). Thirteen of the 19 compounds synthesised were considered active ((50% inhibitory concentration (IC) ≤ 10 µM in two or more test systems)). Increasing alkyl chain length on the hydroxamic acid moiety enhanced activity and morpholinyl-containing derivatives were more active than -acetyl-piperizinyl derivatives. The IC values in cell-based assay systems were comparable to those obtained by direct inhibition of 5-LO activity, confirming that the compounds are direct inhibitors of 5-LO. Particularly, compounds and had outstanding potencies (IC < 1 µM), comparable to that of the prototype 5-LO inhibitor, zileuton. Pronounced activity was demonstrated in zymosan-induced peritonitis in mice. These novel oxazolidinone hydroxamic acid derivatives are, therefore, potent 5-LO inhibitors with potential application as anti-allergic and anti-inflammatory agents.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Hydroxamic Acids; Inflammation; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Oxazolidinones; Structure-Activity Relationship; Zymosan
PubMed: 32635785
DOI: 10.1080/14756366.2020.1786082 -
Molecules (Basel, Switzerland) Jan 2022Complexes that incorporate both ligand(s) and metal(s) exhibiting cytotoxic activity can especially be interesting to develop multifunctional drug molecules with desired... (Review)
Review
Complexes that incorporate both ligand(s) and metal(s) exhibiting cytotoxic activity can especially be interesting to develop multifunctional drug molecules with desired activities. In this review, the limited number of solution results collected in our laboratory on the complexes of Pd(II) and two other platinum group metals-the half-sandwich type, [(η--cym)Ru(HO)], and [(η-Cp*)Rh(HO)]-with hydroxamic acid derivatives of three amino acids, two imidazole analogues, and four small peptides are summarized and evaluated. Unlike the limited number of coordination sites of these metal ions (four and three for Pd(II) and the organometallic cations, respectively), the ligands discussed here offer a relatively high number of donor atoms as well as variation in their position within the ligands, resulting in a large versatility of the likely coordination modes. The review, besides presenting the solution equilibrium results, also discusses the main factors, such as (N,N) versus (O,O) chelate; size of chelate; amino-N versus imidazole-N; primary versus secondary hydroxamic function; differences between hydrolytic ability of the metal ions studied; and hydrolysis of the coordinated peptide hydroxamic acids in their Pd(II) complexes, which all determine the coordination modes present in the complexes formed in measurable concentrations in these systems. The options for the quantitative evaluation of metal binding effectivity and selectivity of the various ligands and the comparison with each other by using solution equilibrium data are also discussed.
Topics: Amino Acids; Chelating Agents; Coordination Complexes; Hydroxamic Acids; Ligands; Models, Molecular; Peptide Fragments; Platinum
PubMed: 35163937
DOI: 10.3390/molecules27030669 -
ChemMedChem Mar 2013The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant... (Review)
Review
The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes. To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio)isosteres. The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biologically active compound or to create new intellectual property. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i.e., the characteristic properties of the drug and the drug-target). As a result, screening of a panel of isosteres is typically required. In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research. The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio)isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design.
Topics: Azoles; Carboxylic Acids; Drug Design; Furans; Hydroxamic Acids; Ketones; Kinetics; Phosphorous Acids; Sulfonamides; Sulfonic Acids
PubMed: 23361977
DOI: 10.1002/cmdc.201200585 -
Gene Nov 2023The role of histone deacetylases (HDACs) in the tumor immune microenvironment of gynecologic tumors remains unexplored. We integrated data from The Cancer Genome Atlas...
The role of histone deacetylases (HDACs) in the tumor immune microenvironment of gynecologic tumors remains unexplored. We integrated data from The Cancer Genome Atlas and Human Protein Atlas to examine HDAC expression in breast, cervical, ovarian, and endometrial cancers. Elevated HDAC expression correlated with poor prognosis and highly malignant cancer subtypes. Gene Set Enrichment Analysis revealed positive associations between HDAC expression and tumor proliferation signature, while negative associations were found with tumor inflammation signature. Increased HDAC expression was linked to reduced infiltration of natural killer (NK), NKT, and CD8 T cells, along with negative associations with the expression of PSMB10, NKG7, CCL5, CD27, HLA-DQA1, and HLA-DQB1. In a murine 4T1 breast cancer model, treatment with suberoylanilide hydroxamic acid (SAHA; HDAC inhibitor) and PD-1 antibody significantly inhibited tumor growth and infiltration of CD3 and CD8 T cells. Real-time polymerase chain reaction revealed upregulated expressions of Psmb10, Nkg7, Ccl5, Cd8a, Cxcr6, and Cxcl9 genes, while Ctnnb1 and Myc genes were inhibited, indicating tumor suppression and immune microenvironment activation. Our study revealed that HDACs play tumor-promoting and immunosuppressive roles in gynecologic cancers, suggesting HDAC inhibitors as potential therapeutic agents for these cancers.
Topics: Female; Humans; Animals; Mice; Histone Deacetylases; Genital Neoplasms, Female; Hydroxamic Acids; CD8-Positive T-Lymphocytes; Vorinostat; Histone Deacetylase Inhibitors; Tumor Microenvironment; Membrane Proteins; Proteasome Endopeptidase Complex
PubMed: 37572797
DOI: 10.1016/j.gene.2023.147704