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International Journal of Molecular... Jul 2022The rapid emergence of antibiotic resistance demands new antimicrobial strategies that are less likely to develop resistance. Augmenting the synthesis of endogenous host...
The rapid emergence of antibiotic resistance demands new antimicrobial strategies that are less likely to develop resistance. Augmenting the synthesis of endogenous host defense peptides (HDPs) has been proven to be an effective host-directed therapeutic approach. This study aimed to identify small-molecule compounds with a strong ability to induce endogenous HDP synthesis for further development as novel antimicrobial agents. By employing a stable HDP promoter-driven luciferase reporter cell line known as HTC/, we performed high-throughput screening of 5002 natural and synthetic compounds and identified 110 hits with a minimum Z-score of 2.0. Although they were structurally and functionally diverse, half of these hits were inhibitors of class I histone deacetylases, the phosphoinositide 3-kinase pathway, ion channels, and dopamine and serotonin receptors. Further validations revealed mocetinostat, a benzamide histone deacetylase inhibitor, to be highly potent in enhancing the expression of multiple HDP genes in chicken macrophage cell lines and jejunal explants. Importantly, mocetinostat was more efficient than entinostat and tucidinostat, two structural analogs, in promoting HDP gene expression and the antibacterial activity of chicken macrophages. Taken together, mocetinostat, with its ability to enhance HDP synthesis and the antibacterial activity of host cells, could be potentially developed as a novel antimicrobial for disease control and prevention.
Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antimicrobial Cationic Peptides; Chickens; Macrophages; Phosphatidylinositol 3-Kinases
PubMed: 35955551
DOI: 10.3390/ijms23158400 -
Leukemia & Lymphoma Mar 2023
Topics: Humans; CREB-Binding Protein; E1A-Associated p300 Protein; Epigenesis, Genetic; Lymphoma, Non-Hodgkin; Mutation; Neoplasm Recurrence, Local
PubMed: 36642966
DOI: 10.1080/10428194.2022.2164194 -
The Lancet. Oncology Dec 2011The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for...
BACKGROUND
The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma.
METHODS
Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982.
FINDINGS
51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment.
INTERPRETATION
Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma.
FUNDING
MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Benzamides; Disease-Free Survival; Drug Administration Schedule; Female; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Kaplan-Meier Estimate; Male; Middle Aged; North America; Pyrimidines; Recurrence; Time Factors; Treatment Outcome; Young Adult
PubMed: 22033282
DOI: 10.1016/S1470-2045(11)70265-0 -
Sarcoma 2018Histone deacetylase inhibitors (HDACi) can reverse chemoresistance, enhance chemotherapy-induced cytotoxicity, and reduce sarcoma proliferation in cell lines and animal...
SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy.
Histone deacetylase inhibitors (HDACi) can reverse chemoresistance, enhance chemotherapy-induced cytotoxicity, and reduce sarcoma proliferation in cell lines and animal models. We sought to determine the safety and toxicity of mocetinostat and its ability to reverse chemoresistance when administered with gemcitabine in patients with metastatic leiomyosarcoma resistant to prior gemcitabine-containing therapy. Participants with metastatic leiomyosarcoma received mocetinostat orally, 70 mg per day, three days per week, increasing to 90 mg after three weeks if well tolerated. Gemcitabine was administered at 1,000 mg/m intravenously at 10 mg/m/minute on days five and 12 of every 21-day cycle. Disease response was evaluated with CT or MRI. Twenty participants with leiomyosarcoma were evaluated for toxicity. Median time to disease progression was 2.0 months (95% CI 1.54-3.12). Eighteen participants were evaluated for radiologic response by RECIST 1.1. Best responses included one PR and 12 SD. Tumor size reduced in 3 patients. Most common toxicities were fatigue, thrombocytopenia, anemia, nausea, and anorexia. One patient experienced a significant pericardial adverse event. No study-related deaths were observed. Rechallenging with gemcitabine by adding mocetinostat was feasible and demonstrated modest activity in patients with leiomyosarcoma. Further studies are needed to better define the role of HDAC inhibitors in patients with metastatic leiomyosarcoma.
PubMed: 30473623
DOI: 10.1155/2018/2068517 -
International Journal of Molecular... May 2015Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking...
BACKGROUND
Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking chromatin remodeling events with observed anti-fibrotic effects are unknown. Here, we investigated the molecular players involved in anti-fibrotic effects of HDAC inhibition in congestive heart failure (CHF) myocardium and cardiac fibroblasts in vivo.
METHODS AND RESULTS
MI was created by coronary artery occlusion. Class I HDACs were inhibited in three-week post MI rats by intraperitoneal injection of Mocetinostat (20 mg/kg/day) for duration of three weeks. Cardiac function and heart tissue were analyzed at six week post-MI. CD90+ cardiac fibroblasts were isolated from ventricles through enzymatic digestion of heart. In vivo treatment of CHF animals with Mocetinostat reduced CHF-dependent up-regulation of HDAC1 and HDAC2 in CHF myocardium, improved cardiac function and decreased scar size and total collagen amount. Moreover, expression of pro-fibrotic markers, collagen-1, fibronectin and Connective Tissue Growth Factor (CTGF) were reduced in the left ventricle (LV) of Mocetinostat-treated CHF hearts. Cardiac fibroblasts isolated from Mocetinostat-treated CHF ventricles showed a decrease in expression of collagen I and III, fibronectin and Timp1. In addition, Mocetinostat attenuated CHF-induced elevation of IL-6 levels in CHF myocardium and cardiac fibroblasts. In parallel, levels of pSTAT3 were reduced via Mocetinostat in CHF myocardium.
CONCLUSIONS
Anti-fibrotic effects of Mocetinostat in CHF are associated with the IL-6/STAT3 signaling pathway. In addition, our study demonstrates in vivo regulation of cardiac fibroblasts via HDAC inhibition.
Topics: Animals; Benzamides; Cicatrix; Collagen; Connective Tissue Growth Factor; Disease Models, Animal; Fibroblasts; Fibronectins; Fibrosis; Gene Expression; Heart Failure; Histone Deacetylase Inhibitors; Histone Deacetylases; Interleukin-6; Myocardial Ischemia; Pyrimidines; Rats; STAT3 Transcription Factor; Signal Transduction; Ventricular Function
PubMed: 25997003
DOI: 10.3390/ijms160511482 -
PloS One 2016Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of...
Profile of Class I Histone Deacetylases (HDAC) by Human Dendritic Cells after Alcohol Consumption and In Vitro Alcohol Treatment and Their Implication in Oxidative Stress: Role of HDAC Inhibitors Trichostatin A and Mocetinostat.
Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of histone deacetylases (HDACs) on alcohol-induced oxidative stress of human primary monocyte-derived dendritic cells (MDDCs) has not been elucidated. In the current study, we took a novel approach combining ex vivo, in vitro and in silico analyses to elucidate the mechanisms of alcohol-induced oxidative stress and role of HDACs in the periphery. ex vivo and in vitro analyses of alcohol-modulation of class I HDACs and activity by MDDCs from self-reported alcohol users and non-alcohol users was performed. Additionally, MDDCs treated with alcohol were assessed using qRT-PCR, western blot, and fluorometric assay. The functional effects of alcohol-induce oxidative stress were measured in vitro using PCR array and in silico using gene expression network analysis. Our findings show, for the first time, that MDDCs from self-reported alcohol users have higher levels of class I HDACs compare to controls and alcohol treatment in vitro differentially modulates HDACs expression. Further, HDAC inhibitors (HDACi) blocked alcohol-induction of class I HDACs and modulated alcohol-induced oxidative stress related genes expressed by MDDCs. In silico analysis revealed new target genes and pathways on the mode of action of alcohol and HDACi. Findings elucidating the ability of alcohol to modulate class I HDACs may be useful for the treatment of alcohol-induced oxidative damage and may delineate new potential immune-modulatory mechanisms.
Topics: Alcohol Drinking; Antioxidants; Benzamides; Dendritic Cells; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; In Vitro Techniques; Male; Oxidative Stress; Pyrimidines; Reactive Oxygen Species
PubMed: 27249803
DOI: 10.1371/journal.pone.0156421 -
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 -
Frontiers in Molecular Biosciences 2022Enhancing the immune microenvironment in cancer by targeting the nucleic acid sensors is becoming a potent therapeutic strategy. Among the nucleic acid sensors,...
Enhancing the immune microenvironment in cancer by targeting the nucleic acid sensors is becoming a potent therapeutic strategy. Among the nucleic acid sensors, activation of the RNA sensor Retinoic Acid-inducible Gene (RIG-I) using small hairpin RNAs has been shown to elicit powerful innate and adaptive immune responses. Given the challenges inherent in pharmacokinetics and delivery of RNA based agonists, we set out to discover small molecule agonists of RIG-I using a cell-based assay. To this end, we established and validated a robust high throughput screening assay based on a commercially available HEK293 reporter cell line with a luciferase reporter downstream of tandem interferon stimulated gene 54 (ISG54) promoter elements. We first confirmed that the luminescence in this cell line is dependent on RIG-I and the interferon receptor using a hairpin RNA RIG-I agonist. We established a 96-well and a 384-well format HTS based on this cell line and performed a proof-of-concept screen using an FDA approved drug library of 1,200 compounds. Surprisingly, we found two HDAC inhibitors Entinostat, Mocetinostat and the PLK1 inhibitor Volasertib significantly enhanced ISG-luciferase activity. This luminescence was substantially diminished in the null reporter cell line indicating the increase in signaling was dependent on RIG-I expression. Combination treatment of tumor cell lines with Entinostat increased RIG-I induced cell death in a mammary carcinoma cell line that is resistant to either Entinostat or RIG-I agonist alone. Taken together, our data indicates an unexpected role for HDAC1,-3 inhibitors in enhancing RIG-I signaling and highlight potential opportunities for therapeutic combinations.
PubMed: 35237663
DOI: 10.3389/fmolb.2022.837610 -
Cancer Genomics & Proteomics 2017Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 gene. It comprises approximately 15-20% of breast... (Review)
Review
Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 gene. It comprises approximately 15-20% of breast cancers (BCs). Unfortunately, TNBC's treatment continues to be a clinical problem because of its relatively poor prognosis, its aggressiveness and the lack of targeted therapies, leaving chemotherapy as the mainstay of treatment. It is essential to find new therapies against TNBC, in order to surpass the resistance and the invasiveness of already existing therapies. Given the fact that epigenetic processes control both the initiation and progression of TNBC, there is an increasing interest in the mechanisms, molecules and signaling pathways that participate at the epigenetic modulation of genes expressed in carcinogenesis. The acetylation of histone proteins provokes the transcription of genes involved in cell growth, and the expression of histone deacetylases (HDACs) is frequently up-regulated in many malignancies. Unfortunately, in the field of BC, HDAC inhibitors have shown limited effect as single agents. Nevertheless, their use in combination with kinase inhibitors, autophagy inhibitors, ionizing radiation, or two HDAC inhibitors together is currently being evaluated. HDAC inhibitors such as suberoylanilidehydroxamic acid (SAHA), sodium butyrate, mocetinostat, panobinostat, entinostat, YCW1 and N-(2-hydroxyphenyl)-2-propylpentanamide have shown promising therapeutic outcomes against TNBC, especially when they are used in combination with other anticancer agents. More studies concerning HDAC inhibitors in breast carcinomas along with a more accurate understanding of the TNBC's pathobiology are required for the possible identification of new therapeutic strategies.
Topics: Antineoplastic Agents; Female; Histone Deacetylases; Humans; Molecular Targeted Therapy; Triple Negative Breast Neoplasms
PubMed: 28870998
DOI: 10.21873/cgp.20041 -
International Journal of Molecular... Jan 2022The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal...
The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal melanocytes or benign nevi. The mechanisms underlying the aberrant expression of BRN3A are unknown. Here, we investigated the epigenetic regulation of in melanocytes and melanoma cell lines treated with DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC) inhibitors. DNMT and HAT inhibition did not significantly alter BRN3A expression levels, whereas panHDAC inhibition by trichostatin A led to increased expression. Treatment with the isoform-specific HDAC inhibitor mocetinostat, but not with PCI-34051, also increased BRN3A expression levels, suggesting that class I HDACs HDAC1, HDAC2, and HDAC3, and class IV HDAC11, were involved in the regulation of BRN3A expression. Transient silencing of HDACs 1, 2, 3, and 11 by siRNAs revealed that, specifically, HDAC2 inhibition was able to increase BRN3A expression. ChIP-Seq analysis uncovered that HDAC2 inhibition specifically increased H3K27ac levels at a distal enhancer region of the gene. Altogether, our data suggest that HDAC2 is a key epigenetic regulator of BRN3A in melanocytes and melanoma cells. These results highlight the importance of epigenetic mechanisms in regulating melanoma oncogenes.
Topics: Cell Line; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Gene Silencing; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Melanocytes; Melanoma; Transcription Factor Brn-3A
PubMed: 35055045
DOI: 10.3390/ijms23020849