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Cancers Dec 2021Inactivating germline mutations in the gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic...
Inactivating germline mutations in the gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking expression. breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. -null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both and deletions. However, the deletion of largely abrogated the sensitivity of the -null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced expression in heterozygous murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic -deficient cancers.
PubMed: 35008338
DOI: 10.3390/cancers14010175 -
Journal of Cardiovascular Pharmacology Feb 2022Over the past decade, histone deacetylases (HDACs) has been proven to manipulate development and exacerbation of cardiovascular diseases, including myocardial...
Isoform-Selective HDAC Inhibitor Mocetinostat (MGCD0103) Alleviates Myocardial Ischemia/Reperfusion Injury Via Mitochondrial Protection Through the HDACs/CREB/PGC-1α Signaling Pathway.
Over the past decade, histone deacetylases (HDACs) has been proven to manipulate development and exacerbation of cardiovascular diseases, including myocardial ischemia/reperfusion injury, cardiac hypertrophy, ventricular remodeling, and myocardial fibrosis. Inhibition of HDACs, especially class-I HDACs, is potent to the protection of ischemic myocardium after ischemia/reperfusion (I/R). Herein, we examine whether mocetinostat (MGCD0103, MOCE), a class-I selective HDAC inhibitor in phase-II clinical trial, shows cardioprotection under I/R in vivo and in vitro, if so, reveal its potential pharmacological mechanism to provide an experimental and theoretical basis for mocetinostat usage in a clinical setting. Human cardiac myocytes (HCMs) were exposed to hypoxia and reoxygenation (H/R), with or without mocetinostat treatment. H/R reduced mitochondrial membrane potential and induced HCMs apoptosis. Mocetinostat pretreatment reversed these H/R-induced mitochondrial damage and cellular apoptosis and upregulated CREB, p-CREB, and PGC-1α in HCMs during H/R. Transfection with small interfering RNA against PGC-1α or CREB abolished the protective effects of mocetinostat on cardiomyocytes undergoing H/R. In vivo, mocetinostat was demonstrated to protect myocardial injury posed by myocardial I/R via the activation of CREB and upregulation of PGC-1α. Mocetinostat (MGCD0103) can protect myocardium from I/R injury through mitochondrial protection mediated by CREB/PGC-1α pathway. Therefore, activation of the CREB/PGC-1α signaling pathway via the inhibition of Class-I HDACs may be a promising new therapeutic strategy for alleviating myocardial reperfusion injury.
Topics: Animals; Apoptosis; Benzamides; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac; Protein Isoforms; Pyrimidines; Rats; Rats, Sprague-Dawley; Signal Transduction
PubMed: 34983914
DOI: 10.1097/FJC.0000000000001174 -
Cells Nov 2021Neonatal porcine islets-like clusters (NPICCs) are a promising source for cell therapy of type 1 diabetes. Freshly isolated NPICCs are composed of progenitor cells and...
Neonatal porcine islets-like clusters (NPICCs) are a promising source for cell therapy of type 1 diabetes. Freshly isolated NPICCs are composed of progenitor cells and endocrine cells, which undergo a maturation process lasting several weeks until the normal beta cell function has developed. Here, we investigated the effects of short-chain fatty acids on the maturation of islet cells isolated from two to three day-old piglets. NPICCs were cultivated with acetate, butyrate and propionate (0-2000 µM) for one to eight days. Incubation with butyrate resulted in a significant upregulation of insulin gene expression and an increased beta cell number, whereas acetate or propionate had only marginal effects. Treatment with specific inhibitors of G-protein-coupled receptor GPR41 (β-hydroxybutyrate) and/or GPR43 (GPLG0974) did not abolish butyrate induced insulin expression. However, incubation of NPICCs with class I histone deacetylase inhibitors (HDACi) mocetinostat and MS275, but not selective class II HDACi (TMP269, MC1568) mimicked the butyrate effect on beta cell differentiation. Our study revealed that butyrate treatment has the capacity to increase the number of beta cells, which may be predominantly mediated through its HDAC inhibitory activity. Butyrate and specific class I HDAC inhibitors may represent beneficial supplements to promote differentiation of neonatal porcine islet cells towards beta cells for cell replacement therapies.
Topics: Animals; Animals, Newborn; Biomarkers; Butyrates; Cell Differentiation; Histone Deacetylase Inhibitors; Histone Deacetylases; Insulin; Insulin-Secreting Cells; Protein Binding; Receptors, G-Protein-Coupled; Swine; Time Factors; Transcription, Genetic; Up-Regulation
PubMed: 34831471
DOI: 10.3390/cells10113249 -
Cancers Sep 2021The aim of this study was to increase somatostatin type-2 receptor (SSTR2) expression on neuroendocrine tumor (NET) cells using histone deacetylase inhibitors (HDACis),...
The aim of this study was to increase somatostatin type-2 receptor (SSTR2) expression on neuroendocrine tumor (NET) cells using histone deacetylase inhibitors (HDACis), potentially increasing the uptake of SSTR2-targeted radiopharmaceuticals and subsequently improving treatment efficacy of peptide receptor radionuclide therapy (PRRT). Human NET cell lines BON-1, NCI-H727, and GOT1 were treated with HDACis (i.e., CI-994, entinostat, LMK-235, mocetinostat, panobinostat, or valproic acid (VPA); entinostat and VPA were the HDACis tested in GOT1 cells) to examine mRNA expression levels and uptake of SSTR2-targeting radiotracer [In]In-DOTATATE. Reversibility of the induced effects was examined after drug-withdrawal. Finally, the effect of VPA on radiosensitivity was investigated. A strong stimulatory effect in BON-1, NCI-H727, and GOT1 cells was observed after HDACi treatment, both on mRNA expression levels and [In]In-DOTATATE uptake. The effects of the HDACis were largely reversible over a period of seven days, demonstrating largest reductions within the first day. The reversibility profile of the induced effects suggests that proper timing of HDACi treatment is most likely essential for a beneficial outcome. In addition to increasing SSTR2 expression levels, VPA enhanced the radiosensitivity of all cell lines. In conclusion, HDACi treatment increased SSTR2 expression, and radiosensitivity was also enhanced upon VPA treatment.
PubMed: 34638389
DOI: 10.3390/cancers13194905 -
Archives of Biochemistry and Biophysics Nov 2021Human epidermal growth factor receptor 2 (HER2)-positive breast cancer represents approximately 15-30% of all invasive breast cancers. Despite the recent advances in...
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer represents approximately 15-30% of all invasive breast cancers. Despite the recent advances in therapeutic practices of HER2 subtype, drug resistance and tumor recurrence still have remained as major problems. Drug discovery is a long and difficult process, so the aim of this study is to find potential new application for existing therapeutic agents. Gene expression data for breast invasive carcinoma were retrieved from The Cancer Genome Atlas (TCGA) database. The normal and tumor samples were analyzed using Linear Models for Microarray Data (LIMMA) R package in order to find the differentially expressed genes (DEGs). These genes were used as entry for the library of integrated network-based cellular signatures (LINCS) L1000CDS software and suggested 24 repurposed drugs. According to the obtained results, some of these drugs including vorinostat, mocetinostat, alvocidib, CGP-60474, BMS-387032, AT-7519, and curcumin have significant functional similarity and structural correlation with FDA-approved breast cancer drugs. Based on the drug-target network, which consisted of the repurposed drugs and their target genes, the aforementioned drugs had the highest degrees. Moreover, the experimental approach verified curcumin as an effective therapeutic agent for HER2 positive breast cancer. Hence, our work suggested that some repurposed drugs based on gene expression data can be noticed as potential drugs for the treatment of HER2-positive breast cancer.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Databases, Genetic; Drug Repositioning; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Receptor, ErbB-2
PubMed: 34597657
DOI: 10.1016/j.abb.2021.109043 -
Reviews in Cardiovascular Medicine Sep 2021Histone deacetylase (HDAC) inhibitors have shown cardioprotective or renoprotective effects in various animal models. Our study proposed that the HDAC inhibitor,...
Histone deacetylase inhibitor, mocetinostat, regulates cardiac remodelling and renin-angiotensin system activity in rats with transverse aortic constriction-induced pressure overload cardiac hypertrophy.
Histone deacetylase (HDAC) inhibitors have shown cardioprotective or renoprotective effects in various animal models. Our study proposed that the HDAC inhibitor, mocetinostat, regulates cardiac remodelling and renin-angiotensin system (RAS) activity in rats with transverse aortic constriction (TAC)-induced pressure overload cardiac hypertrophy. Cardiac remodelling was evaluated using echocardiography. Cardiac hypertrophy was visualized with haematoxylin and eosin staining, and related gene ( and ) expression was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Cardiac and renal fibrosis were visualized with picrosirius red and trichrome staining, respectively. Fibrosis related gene (, , , and ) expression was determined by qRT-PCR. Serum concentrations of RAS components (renin, angiotensin II, and aldosterone) were quantified by enzyme-linked immunosorbent assay and related gene ( and ) expression was determined by qRT-PCR. TAC-induced pressure overload cardiac hypertrophy, which mimics hypertensive heart disease, increased cardiac remodelling, cardiac hypertrophy, and fibrosis in our rat models. Upon treatment with mocetinostat, there was a significant regression in cardiac remodelling, cardiac hypertrophy, and fibrosis in TAC rats. Additionally, pressure overload-induced renal fibrosis and activity of RAS-related components were increased in TAC rats, and were decreased on treatment with mocetinostat. The present study indicates that mocetinostat, an HDAC inhibitor, has cardiorenal protective effects in rats with TAC-induced pressure overload cardiac hypertrophy and offers a promising therapeutic agent for hypertension-related diseases.
Topics: Animals; Benzamides; Cardiomegaly; Constriction; Fibrosis; Histone Deacetylase Inhibitors; Humans; Myocardium; Pyrimidines; Rats; Renin-Angiotensin System; Ventricular Remodeling
PubMed: 34565105
DOI: 10.31083/j.rcm2203113 -
Computers in Biology and Medicine Oct 2021Histone deacetylases (HDACs) as an important family of epigenetic regulatory enzymes are implicated in the onset and progression of carcinomas. As a result, HDAC...
Histone deacetylases (HDACs) as an important family of epigenetic regulatory enzymes are implicated in the onset and progression of carcinomas. As a result, HDAC inhibition has been proven as a compelling strategy for reversing the aberrant epigenetic changes associated with cancer. However, non-selective profile of most developed HDAC inhibitors (HDACIs) leads to the occurrence of various side effects, limiting their clinical utility. This evidence provides a solid ground for ongoing research aimed at identifying isoform-selective inhibitors. Among the isoforms, HDAC1 have particularly gained increased attention as a preferred target for the design of selective HDACIs. Accordingly, in this paper, we have developed a reliable virtual screening process, combining different ligand- and structure-based methods, to identify novel benzamide-based analogs with potential HDAC1 inhibitory activity. For this purpose, a focused library of 736,160 compounds from PubChem database was first compiled based on 80% structural similarity with four known benzamide-based HDAC1 inhibitors, Mocetinostat, Entinostat, Tacedinaline, and Chidamide. Our inclusive in-house 3D-QSAR model, derived from pharmacophore-based alignment, was then employed as a 3D-query to discriminate hits with the highest predicted HDAC1 inhibitory activity. The selected hits were subjected to subsequent structure-based approaches (induced-fit docking (IFD), MM-GBSA calculations and molecular dynamics (MD) simulation) to retrieve potential compounds with the highest binding affinity for HDAC1 active site. Additionally, in silico ADMET properties and PAINS filtration were also considered for selecting an enriched set of the best drug-like molecules. Finally, six top-ranked hit molecules, CID_38265326, CID_56064109, CID_8136932, CID_55802151, CID_133901641 and CID_18150975 were identified to expose the best stability profiles and binding mode in the HDAC1 active site. The IFD and MD results cooperatively confirmed the interactions of the promising selected hits with critical residues within HDAC1 active site. In summary, the presented computational approach can provide a set of guidelines for the further development of improved benzamide-based derivatives targeting HDAC1 isoform.
Topics: Histone Deacetylase Inhibitors; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Quantitative Structure-Activity Relationship
PubMed: 34478925
DOI: 10.1016/j.compbiomed.2021.104808 -
Nature Communications Jul 2021The epithelial-mesenchymal transition (EMT) has been implicated in conferring stem cell properties and therapeutic resistance to cancer cells. Therefore, identification...
The epithelial-mesenchymal transition (EMT) has been implicated in conferring stem cell properties and therapeutic resistance to cancer cells. Therefore, identification of drugs that can reprogram EMT may provide new therapeutic strategies. Here, we report that cells derived from claudin-low mammary tumors, a mesenchymal subtype of triple-negative breast cancer, exhibit a distinctive organoid structure with extended "spikes" in 3D matrices. Upon a miR-200 induced mesenchymal-epithelial transition (MET), the organoids switch to a smoother round morphology. Based on these observations, we developed a morphological screening method with accompanying analytical pipelines that leverage deep neural networks and nearest neighborhood classification to screen for EMT-reversing drugs. Through screening of a targeted epigenetic drug library, we identified multiple class I HDAC inhibitors and Bromodomain inhibitors that reverse EMT. These data support the use of morphological screening of mesenchymal mammary tumor organoids as a platform to identify drugs that reverse EMT.
Topics: Animals; Antineoplastic Agents; Azacitidine; Benzamides; Drug Screening Assays, Antitumor; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Image Processing, Computer-Assisted; Mammary Neoplasms, Animal; Mesoderm; Mice, Inbred BALB C; MicroRNAs; Neoplasm Proteins; Organoids; Pyrimidines; Reproducibility of Results; Small Molecule Libraries; Mice
PubMed: 34253738
DOI: 10.1038/s41467-021-24545-3 -
European Review For Medical and... May 2021The article "Mocetinostat suppresses epidural fibrosis following laminectomy by inhibiting myofibroblast activation and increasing apoptosis, by W.-J. Wu, J. Wang, J....
The article "Mocetinostat suppresses epidural fibrosis following laminectomy by inhibiting myofibroblast activation and increasing apoptosis, by W.-J. Wu, J. Wang, J. Liang, Q. Zhou, Y. Liang, published in Eur Rev Med Pharmacol Sci 2020; 24 (8): 4467-4475-DOI: 10.26355/eurrev_202004_21029-PMID: 32373984" has been withdrawn from the authors due to some errors in the data. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/21029.
PubMed: 34002805
DOI: 10.26355/eurrev_202105_25801 -
IEEE/ACM Transactions on Computational... 2021COVID-19 is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The case-fatality rate is significantly higher in...
COVID-19 is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The case-fatality rate is significantly higher in older patients and those with diabetes, cancer or cardiovascular disorders. The human proteins, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2) and basigin (BSG), are involved in high-confidence host-pathogen interactions with SARS-CoV-2 proteins. We considered these three proteins as seed nodes and applied the random walk with restart method on the human interactome to construct a protein-protein interaction sub-network, which captures the effects of viral invasion. We found that 'Insulin resistance', 'AGE-RAGE signaling in diabetic complications' and 'adipocytokine signaling' were the common pathways associated with diabetes, cancer and cardiovascular disorders. The association of these critical pathways with aging and its related diseases explains the molecular basis of COVID-19 fatality. We further identified drugs that have effects on these proteins/pathways based on gene expression studies. We particularly focused on drugs that significantly downregulate ACE2 along with other critical proteins identified by the network-based approach. Among them, COL-3 had earlier shown activity against acute lung injury and acute respiratory distress, while entinostat and mocetinostat have been investigated for non-small-cell lung cancer. We propose that these drugs can be repurposed for COVID-19.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; COVID-19; Cardiovascular Diseases; Comorbidity; Computational Biology; Drug Repositioning; Gastrointestinal Diseases; Gene Expression Profiling; Host Microbial Interactions; Humans; Pandemics; Protein Interaction Maps; Respiratory Tract Diseases; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33891554
DOI: 10.1109/TCBB.2021.3075299