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JCI Insight Sep 2023Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is...
Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat - a class I selective histone deacetylase (HDAC) inhibitor - had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD.
Topics: Humans; Animals; Mice; Kruppel-Like Factor 4; Osteoarthritis; Inflammation; Histone Deacetylase Inhibitors; Bone Neoplasms
PubMed: 37681413
DOI: 10.1172/jci.insight.170513 -
European Review For Medical and... Apr 2020To investigate the effect and mechanism of mocetinostat on diminishing epidural fibrosis. Dysregulated wound repair usually occurs after injury or surgery and is...
OBJECTIVE
To investigate the effect and mechanism of mocetinostat on diminishing epidural fibrosis. Dysregulated wound repair usually occurs after injury or surgery and is featured by excessive scar tissue contributed by fibrosis. Increasing researches demonstrated that histone acetylation, an epigenetic alteration, plays a crucial role in fibrosis. However, the mechanism of the complicated process remains unclear. In the current study, the effect of histone deacetylase (HDAC) inhibitor mocetinostat in a rat model of epidural fibrosis was detected, and it was discovered that mocetinostat suppressed myofibroblast activation and increased apoptosis by reducing Akt/GSK3b signaling.
PATIENTS AND METHODS
First, the levels of histone acetylation in the patients' epidural fibroblasts were analyzed. Then, mRNAs and proteins obtained from human fibroblasts following TGF-β activation and mocetinostat treatment in vitro were used to examine the influence of mocetinostat on the activation and survival of fibroblasts, so as to explore the related mechanism of mocetinostat. The laminectomy model was established in rats to observe the therapeutic effect of mocetinostat on epidural scar tissues.
RESULTS
In this research, it was found that the increase of HDAC1 in human dura scar was accompanied by the aggravation of fibrosis. In addition, cell assay demonstrated that mocetinostat inhibited fibroblast activation and accelerated apoptosis by inhibiting Akt/GSK3b pathway. In the rat model, mocetinostat weakened scar hyperplasia and collagen deposition and effectively inhibited the process of epidural fibrosis.
CONCLUSIONS
The above results indicate that mocetinostat inhibits HDAC1 expression and decreases the conduction of the AKT/GSK3b pathway in fibroblasts, leading to myofibroblast activation and apoptosis elevation. Hence, mocetinostat ameliorates epidural fibrosis.
Topics: Animals; Apoptosis; Benzamides; Cells, Cultured; Epidural Space; Fibrosis; Humans; Laminectomy; Myofibroblasts; Pyrimidines; Rats; Rats, Sprague-Dawley
PubMed: 32373984
DOI: 10.26355/eurrev_202004_21029 -
Clinical Lung Cancer May 2023Histone deacetylase (HDAC) inhibitors have potential to augment the effectiveness of immune checkpoint inhibitors and overcome treatment resistance. This...
BACKGROUND
Histone deacetylase (HDAC) inhibitors have potential to augment the effectiveness of immune checkpoint inhibitors and overcome treatment resistance. This dose-escalation/expansion study (NCT02805660) investigated mocetinostat (class I/IV HDAC inhibitor) plus durvalumab in patients with advanced non-small cell lung cancer (NSCLC) across cohorts defined by tumor programmed death-ligand 1 (PD-L1) expression and prior experience with anti-programmed cell death protein-1 (anti-PD-1) or anti-PD-L1 regimens.
PATIENTS AND METHODS
Sequential cohorts of patients with solid tumors received mocetinostat (starting dose: 50 mg TIW) plus durvalumab at a standard dose (1500 mg Q4W) to determine the recommended phase II dose (RP2D: phase I primary endpoint), based on the observed safety profile. RP2D was administered to patients with advanced NSCLC across 4 cohorts grouped by tumor PD-L1 expression (none or low/high) and prior experience with anti-PD-L1 /anti-PD-1 agents (naïve, clinical benefit: yes/no). The phase II primary endpoint was objective response rate (ORR, RECIST v1.1).
RESULTS
Eighty-three patients were enrolled (phase I [n = 20], phase II [n = 63]). RP2D was mocetinostat 70 mg TIW plus durvalumab. ORR was 11.5% across the phase II cohorts, and responses were durable (median 329 days). Clinical activity was observed in NSCLC patients with disease refractory to prior checkpoint inhibitor treatment: ORR 23.1%. Across all patients, fatigue (41%), nausea (40%), and diarrhea (31%) were the most frequent treatment-related adverse events.
CONCLUSION
Mocetinostat 70 mg TIW plus durvalumab at the standard dose was generally well tolerated. Clinical activity was observed in patients with NSCLC unresponsive to prior anti-PD-(L)1 therapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Antibodies, Monoclonal; B7-H1 Antigen
PubMed: 36890020
DOI: 10.1016/j.cllc.2023.01.013 -
Expert Opinion on Investigational Drugs Jun 2011HDAC inhibitors (HDACIs) have the potential to restore gene expression and display antitumor effects in vitro. As single agents, HDACIs have clinical activity in... (Review)
Review
INTRODUCTION
HDAC inhibitors (HDACIs) have the potential to restore gene expression and display antitumor effects in vitro. As single agents, HDACIs have clinical activity in lymphoma. In myeloid leukemias, combinations of DNA methylation inhibitors and HDACIs are promising. Other combinations are being studied in solid tumors.
AREAS COVERED
This article covers basic information and an update on preclinical and clinical experience with the oral isotype-selective HDACI MGCD0103 (mocetinostat) in hematological malignancies and solid tumors. It also examines data concerning MGCD0103 from recent conferences and articles through to November 2010, including new data regarding responses in lymphoma and toxicities.
EXPERT OPINION
MGCD0103 is well-tolerated and exhibits favorable pharmacokinetic and pharmacodynamic profiles, demonstrating target inhibition and clinical responses. It induces cell death and autophagy, synergizes with proteasomal inhibitors and affects non-histone targets, such as microtubules. In 2008, new patient enrollment in trials was temporarily suspended due to potential cardiac complications. This restriction was lifted in 2009 as no correlation between MGCD0103 exposure and pericardial effusions was found. New patient enrollment in MGCD0103 clinical trials requires the exclusion of patients diagnosed with significant cardiac abnormalities prior to enrollment. Clinical and pharmacodynamic data support a three-times-weekly administration at a 90 mg fixed dose. MGCD0103 displays promising antitumor activity in several hematological diseases.
Topics: Animals; Antineoplastic Agents; Autophagy; Benzamides; Cell Death; Clinical Trials as Topic; Hematologic Neoplasms; Histone Deacetylase Inhibitors; Humans; Neoplasms; Pyrimidines
PubMed: 21554162
DOI: 10.1517/13543784.2011.577737 -
PloS One 2017Leiomyosarcoma (LMS) is a malignant soft tissue sarcoma (STS) with a dismal prognosis following metastatic disease. Chemotherapeutic intervention has demonstrated to...
Leiomyosarcoma (LMS) is a malignant soft tissue sarcoma (STS) with a dismal prognosis following metastatic disease. Chemotherapeutic intervention has demonstrated to have modest clinical efficacy with no curative potential in LMS patients. Previously, we demonstrated pan-HDAC inhibition to have a superior effect in various complex karyotypic sarcomas. In this study, our goal is to evaluate the therapeutic efficacy of mocetinostat alone and in combination with gemcitabine in LMS. Human leiomyosarcoma (LMS) cell lines were used for in vitro and in vivo studies. Compounds tested included the class I HDAC inhibitor, mocetinostat, and nucleoside analog, gemcitabine. MTS and clonogenic assays were used to evaluate the effect of mocetinostat on LMS cell growth. Cleaved caspase 3/7 analysis was used to determine the effects of mocetinostat on apoptosis. Compusyn software was used to determine in vitro synergy studies for the combination of mocetinostat plus gemcitabine. A LMS xenograft model in SCID mice was used to test the impact of mocetinostat alone, gemcitabine alone and the combination of mocetinostat plus gemcitabine. Mocetinostat abrogated LMS cell growth and clonogenic potential, and enhanced apoptosis in LMS cell lines. The combination of mocetinostat plus gemcitabine exhibited a synergistic effect in LMS cells in vitro. Similarly, mocetinostat combined with gemcitabine resulted in superior anti-LMS effects in vivo. Mocetinostat reduced the expression of gemcitabine-resistance markers RRM1, RRM2, and increased the expression of gemcitabine-sensitivity marker, hENT1, in LMS cells. LMS are aggressive, metastatic tumors with poor prognosis where effective therapeutic interventions are wanting. Our studies demonstrate the potential utility of mocetinostat combined with gemcitabine for the treatment of LMS.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Cell Division; Cell Line, Tumor; Deoxycytidine; Drug Synergism; Humans; Leiomyosarcoma; Pyrimidines; Gemcitabine
PubMed: 29186204
DOI: 10.1371/journal.pone.0188859 -
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 -
Cancer Feb 2019The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in...
BACKGROUND
The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study.
METHODS
Eligible patients with platinum-treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28-day cycles in a 3-stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.
RESULTS
Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent-to-treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose-normalized maximum serum concentration [C ] after TIW dosing of 0.2 ng/mL/mg).
CONCLUSIONS
To the authors' knowledge, the current study represents the first clinical trial using genomic-based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.
Topics: Adult; Aged; Aged, 80 and over; Benzamides; Biomarkers, Tumor; CREB-Binding Protein; Carcinoma, Transitional Cell; E1A-Associated p300 Protein; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Male; Middle Aged; Mutation; Prognosis; Pyrimidines; Urologic Neoplasms
PubMed: 30570744
DOI: 10.1002/cncr.31817 -
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 -
Research Square Apr 2024Histon deacetylase (HDAC) enzyme is one of the enzymes involved in regulating gene expression and epigenetic alternation of cells by removing acetyl groups from lysine...
Histon deacetylase (HDAC) enzyme is one of the enzymes involved in regulating gene expression and epigenetic alternation of cells by removing acetyl groups from lysine residue on a histone, allowing the histones to wrap the DNA more tightly and suppressing a tumor-suppressing gene. HDAC inhibitors play an important role in inhibiting the proliferation of tumor cells by restricting the mechanism of action of HDAC enzyme, leading to the addition of acetyl groups to lysine. Mocetinostat, also known by its chemical name (MGCD0103), is a novel isotype selective HDAC enzyme that explicitly targets HDAC isoforms inhibiting Class1(HDAC 1,2,3,8) and Class IV (HDAC11) enzymes. It was approved for treating the phase II trial of Hodgkin's lymphoma in 2010. Our study revealed that different doses of Mocetinostat inhibit the growth of glioblastoma cells, metastasis, and angiogenesis and induce the apoptosis and differentiation of glioblastoma cells C6 and T98G. Western blot has shown that MGCD0103 has many biological activities to control glioblastoma cancer cells. MGCD0103 can modulate the molecular mechanism for several pathways in cells, such as inhibition of the PI3K/AKT pathway and suppression of HDAC1 enzyme activity in charge of many biological processes in the initiation and progression of cancer. The high doses of Mocetinostat drug significantly induce apoptosis and suppress cancer cell proliferation through increased pro-apoptotic proteins (BAX) and a down level of anti-apoptotic proteins(Bid, Bcl2). Also, the mocetinostat upregulated the expression of the tumor suppressor gene and downregulated the gene expression of the E2f1 transcription factor. Additionally, MGCDO103-induced differentiation was facilitated by activating the differentiation marker GFAP and preventing the undifferentiation marker from expression (Id2, N-Myc). The MGCD0103 is a potent anticancer drug crucial in treating glioblastoma cells.
PubMed: 38645087
DOI: 10.21203/rs.3.rs-4170668/v1 -
Cell Death Discovery 2016The class I selective inhibitor of the histone deacetylases, mocetinostat, has promising antitumor activities in both preclinical studies and the clinical trials. To...
The class I selective inhibitor of the histone deacetylases, mocetinostat, has promising antitumor activities in both preclinical studies and the clinical trials. To understand how mocetinostat induces apoptosis, we examined the effects of mocetinostat on miR-31, a proapoptotic microRNA that was previously found to be epigenetically silenced in prostate cancer. We found that miR-31 was significantly upregulated by mocetinostat in prostate cancer cells. Antiapoptotic protein E2F6, the target of miR-31, was decreased by mocetinostat treatment. When miR-31 was blocked with an inhibitor, the ability of mocetinostat to induce apoptosis was reduced. We further demonstrated that mocetinostat enhanced the activity of docetaxel in apoptosis induction. While siRNA knockdown of E2F6 sensitized cancer cells to mocetinostat-induced apoptosis, overexpression of E2F6 blocked mocetinostat-induced apoptosis. In an orthotopic xenograft model, we demonstrated that mocetinostat activated miR-31, decreased E2F6, induced apoptosis, and significantly reduced prostate cancer growth. Importantly, we found that mocetinostat also increased miR-31 expression, decreased E2F6, and induced apoptosis in the primary prostate cancer stem cells. Thus, activation of miR-31 and downregulation of E2F6 constitute an important mechanism in mocetinostat-induced apoptosis in prostate cancer.
PubMed: 27551526
DOI: 10.1038/cddiscovery.2016.36