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International Immunopharmacology Jun 2024A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE)....
Induction of indoleamine 2,3-dioxygenase 1 expression in neurons of the central nervous system through inhibition of histone deacetylases blocks the progression of experimental autoimmune encephalomyelitis.
BACKGROUND
A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE). However, it is not known whether HDAC inhibition is linked to the AHR signaling pathway in EAE.
METHODS
We investigated how the pan-HDAC inhibitor SB939 (pracinostat) exerted immunoregulatory action in the myelin oligodendrocyte glycoprotein 35-55 (MOG)-induced EAE mouse model by evaluating changes in of signal transducer and activator of transcription 3 (STAT3) acetylation and the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and AHR in inflamed spinal cords during EAE evolution. We proved the involvement of IDO1 and the AHR in SB939-mediated immunosuppression using Ido1 and Ahr mice.
RESULTS
Administration with SB939 halted EAE progression, which depended upon IDO1 expression in neurons of the central nervous system (CNS). Our in vitro and in vivo studies demonstrated that SB939 sustained the interleukin-6-induced acetylation of STAT3, resulting in the stable transcriptional activation of Ido1. The therapeutic effect of SB939 also required the AHR, which is expressed mainly in CD4 T cells and macrophages in CNS disease lesions. Finally, SB939 was shown to markedly reduce the proliferation of CD4 T cells in inflamed neuronal tissues but not in the spleen or draining lymph nodes.
CONCLUSIONS
Overall, our results suggest that IDO1 tryptophan metabolites produced by neuronal cells may act on AHR in pathogenic CD4 T cells in a paracrine fashion in the CNS and that the specific induction of IDO1 expression in neurons at disease-afflicted sites can be considered a therapeutic approach to block the progression of multiple sclerosis without affecting systemic immunity.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Indoleamine-Pyrrole 2,3,-Dioxygenase; Histone Deacetylase Inhibitors; STAT3 Transcription Factor; Mice, Inbred C57BL; Neurons; Mice, Knockout; Mice; Receptors, Aryl Hydrocarbon; Female; Spinal Cord; Myelin-Oligodendrocyte Glycoprotein; Central Nervous System; Hydroxamic Acids; Disease Progression; Histone Deacetylases; Peptide Fragments; Basic Helix-Loop-Helix Transcription Factors; Interleukin-6
PubMed: 38759372
DOI: 10.1016/j.intimp.2024.112246 -
Leukemia Research May 2024Non-intensive therapies such as the hypomethylating agent (HMA) azacitidine (AZA) have been used in patients with AML ineligible for intensive induction chemotherapy... (Randomized Controlled Trial)
Randomized Controlled Trial
Non-intensive therapies such as the hypomethylating agent (HMA) azacitidine (AZA) have been used in patients with AML ineligible for intensive induction chemotherapy (IC) or stem cell transplant due to advanced age, comorbidities, and/or risk factors. However, response rates and survival remain dismal. Pre-clinical studies indicate the epigenetic combination of HMAs and HDAC inhibitors induce re-expression of silenced genes synergistically. The activity of pracinostat, an oral pan-HDAC inhibitor, has been shown in xenograft tumor models of AML and promising efficacy was seen in a Phase 2 study. This Phase 3 study (NCT03151408) evaluated the efficacy/safety of pracinostat administered with AZA in adult patients with newly diagnosed AML ineligible to receive IC. Patients were randomized to either pracinostat plus AZA or placebo/AZA and stratified by cytogenetic risk and ECOG status. As planned, an interim analysis was performed when 232/390 events (deaths) occurred. A total of 406 patients were randomized (203/group) at the time of the analysis. Median overall survival was 9.95 months for both treatment groups (p=0.8275). There was no significant difference between treatments in secondary efficacy endpoints, reflecting a lack of clinical response. This study did not show a benefit of adding pracinostat to AZA in elderly patients unfit for IC.
Topics: Humans; Leukemia, Myeloid, Acute; Male; Aged; Female; Middle Aged; Azacitidine; Antineoplastic Combined Chemotherapy Protocols; Adult; Aged, 80 and over; Induction Chemotherapy; Aminopyridines; Benzamides
PubMed: 38499457
DOI: 10.1016/j.leukres.2024.107480 -
Journal of Enzyme Inhibition and... Dec 2024A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor,...
Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer.
A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound , containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC = 16 nM and 1.03 µM, respectively). Compound also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC, 4.9 nM). Moreover, inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers , was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.
Topics: Mice; Animals; Humans; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Histone Deacetylase Inhibitors; Mice, Nude; Lung Neoplasms; Cell Proliferation; Protein Kinase Inhibitors; Antineoplastic Agents; Cell Line, Tumor
PubMed: 38465731
DOI: 10.1080/14756366.2024.2318645 -
ALDH1A3 contributes to tumorigenesis in high-grade serous ovarian cancer by epigenetic modification.Cellular Signalling Apr 2024High-grade serous ovarian cancer (HGSOC) is the most lethal histotype of ovarian cancer due to its unspecific symptoms in part. ALDH1A3 (aldehyde dehydrogenase 1 family...
High-grade serous ovarian cancer (HGSOC) is the most lethal histotype of ovarian cancer due to its unspecific symptoms in part. ALDH1A3 (aldehyde dehydrogenase 1 family member A3) is a key enzyme for acetyl-CoA production involving aggressive behaviors of cancers. However, ALDH1A3's effects and molecular mechanisms in HGSOC remain to be clarified. Using RNA-seq and publicly available datasets, ALDH1A3 was found to be highly expressed in HGSOC, and associated with poor survival. Knockdown of ALDH1A3 prevented HGSOC tumorigenesis and enhanced cell sensitivity to paclitaxel or cisplatin. ALDH1A3 expression in HGSOC cells was found to be increased by hypoxia, but decreased by HIF-1α inhibitor KC7F2. The dual-luciferase reporter assay showed that the increased transcriptional activity of ALDH1A3 induced by HIF-1α overexpression was reduced by KC7F2. In addition, PITX1 (paired like homeodomain 1) was identified to be inhibited by ALDH1A3 knockdown, and PITX1 depletion inhibited cell proliferation. The mechanistic studies showed that ALDH1A3 knockdown reduced the acetylation of histone 3 lysine 27 (H3K27ac). Treatment of exogenous acetate with NaOAc or inhibition of histone deacetylase with Pracinostat increased H3K27ac and PITX1 levels. CHIP assay demonstrated a significant enrichment of H3K27ac at the PITX1 promoter, and ALDH1A3 knockdown reduced the binding between H3K27ac and PITX1. Taken together, our data suggest that ALDH1A3, transcriptional activated by HIF-1α, promotes tumorigenesis and decreases chemosensitivity by increasing H3K27ac of PITX1 promoter in HGSOC.
Topics: Female; Humans; Carcinogenesis; Cell Transformation, Neoplastic; Ovarian Neoplasms; Epigenesis, Genetic; Acetylation
PubMed: 38211842
DOI: 10.1016/j.cellsig.2024.111044 -
Journal of Pharmaceutical Analysis Oct 2023Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of...
Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of excessively asymmetric mitofission-associated cell death (MFAD) by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy. By screening a series of pan-inhibitors, we identified pracinostat, a pan-histone deacetylase (HDAC) inhibitor, as a novel MFAD inducer, that exhibited a significant anticancer effect on colorectal cancer (CRC) in vivo and in vitro. Pracinostat increased the expression of cyclin-dependent kinase 5 (CDK5) and induced its acetylation at residue lysine 33, accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynamin-related protein 1 (Drp1)-mediated mitochondrial peripheral fission. CRC cells with high level of CDK5 (CDK5-high) displayed midzone mitochondrial division that was associated with oncogenic phenotype, but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells. Mechanistically, pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor (MFF) to mitochondrial fission 1 protein (FIS1). Thus, our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.
PubMed: 38024857
DOI: 10.1016/j.jpha.2023.06.005 -
Brain Sciences Sep 2023The relationship between N6-methyladenosine (m6A) regulators and anoikis and their effects on low-grade glioma (LGG) is not clear yet. The TCGA-LGG cohort, mRNAseq 325...
The relationship between N6-methyladenosine (m6A) regulators and anoikis and their effects on low-grade glioma (LGG) is not clear yet. The TCGA-LGG cohort, mRNAseq 325 dataset, and GSE16011 validation set were separately obtained via the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Altas (CGGA), and Gene Expression Omnibus (GEO) databases. In total, 27 m6A-related genes (m6A-RGs) and 508 anoikis-related genes (ANRGs) were extracted from published articles individually. First, differentially expressed genes (DEGs) between LGG and normal samples were sifted out by differential expression analysis. DEGs were respectively intersected with m6A-RGs and ANRGs to acquire differentially expressed m6A-RGs (DE-m6A-RGs) and differentially expressed ANRGs (DE-ANRGs). A correlation analysis of DE-m6A-RGs and DE-ANRGs was performed to obtain DE-m6A-ANRGs. Next, univariate Cox and least absolute shrinkage and selection operator (LASSO) were performed on DE-m6A-ANRGs to sift out risk model genes, and a risk score was gained according to them. Then, gene set enrichment analysis (GSEA) was implemented based on risk model genes. After that, we constructed an independent prognostic model and performed immune infiltration analysis and drug sensitivity analysis. Finally, an mRNA-miRNA-lncRNA regulatory network was constructed. There were 6901 DEGs between LGG and normal samples. Six DE-m6A-RGs and 214 DE-ANRGs were gained through intersecting DEGs with m6A-RGs and ANRGs, respectively. A total of 149 DE-m6A-ANRGs were derived after correlation analysis. Four genes, namely ANXA5, KIF18A, BRCA1, and HOXA10, composed the risk model, and they were involved in apoptosis, fatty acid metabolism, and glycolysis. The age and risk scores were finally sifted out to construct an independent prognostic model. Activated CD4 T cells, gamma delta T cells, and natural killer T cells had the largest positive correlations with risk model genes, while activated B cells were significantly negatively correlated with KIF18A and BRCA1. AT.9283, EXEL.2280, Gilteritinib, and Pracinostat had the largest correlation (absolute value) with a risk score. Four risk model genes (mRNAs), 12 miRNAs, and 21 lncRNAs formed an mRNA-miRNA-lncRNA network, containing HOXA10-hsa-miR-129-5p-LINC00689 and KIF18A-hsa-miR-221-3p-DANCR. Through bioinformatics, we constructed a prognostic model of m6A-associated anoikis genes in LGG, providing new ideas for research related to the prognosis and treatment of LGG.
PubMed: 37759912
DOI: 10.3390/brainsci13091311 -
Frontiers in Immunology 2023Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy,... (Review)
Review
Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy and immunotherapy. In recent years, immunotherapy has potentiated the survival of certain breast cancer patients; however, primary resistance or acquired resistance attenuate the therapeutic outcomes. Histone acetyltransferases induce histone acetylation on lysine residues, which can be reversed by histone deacetylases (HDACs). Dysregulation of HDACs mutation and abnormal expression contributes to tumorigenesis and tumor progression. Numerous HDAC inhibitors have been developed and exhibited the potent anti-tumor activity in a variety of cancers, including breast cancer. HDAC inhibitors ameliorated immunotherapeutic efficacy in cancer patients. In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer.
Topics: Humans; Female; Histone Deacetylases; Histone Deacetylase Inhibitors; Breast Neoplasms; Vorinostat; Immunotherapy
PubMed: 36969235
DOI: 10.3389/fimmu.2023.1164514 -
Leukemia Research Dec 2022
Topics: Humans; Gemtuzumab; Benzimidazoles; Leukemia, Myeloid, Acute
PubMed: 36401944
DOI: 10.1016/j.leukres.2022.106984 -
Life Sciences Nov 2022Breast cancer (BC) accounts for the majority of cancers among the female population. Anomalous activation of various signaling pathways has become an issue of concern.... (Review)
Review
INTRODUCTION
Breast cancer (BC) accounts for the majority of cancers among the female population. Anomalous activation of various signaling pathways has become an issue of concern. The JAK-STAT signaling pathway is activated in numerous cancers, including BC. STAT3 is widely involved in BCs, as 40 % of BCs display phosphorylated STAT3. JAK-STAT signaling is crucial for proliferation, survival, metastasis and other cellular events associated with the tumor microenvironment. Hence, targeting this pathway has become an area of interest among researchers.
KEY FINDINGS
This review article focuses on the role of STAT3 in the initiation, proliferation, progression and metastasis of BC. The roles of various phytochemicals, synthetic molecules and biologicals against JAK-STAT and STAT3 in various cancers have been discussed, with special emphasis on BC.
SIGNIFICANCE
JAK and STAT3 are involved in various phases from initiation to metastasis, and targeting this pathway is a promising approach to inhibit the various stages of BC development and to prevent metastasis. A number of phytochemicals and synthetic and biological molecules have demonstrated potential inhibitory effects on JAK and STAT3, thereby paving the way for the development of better therapeutics against BC.
Topics: Female; Humans; Breast Neoplasms; STAT3 Transcription Factor; Signal Transduction; Tumor Microenvironment; Cell Proliferation; Phytochemicals; Janus Kinases
PubMed: 36170890
DOI: 10.1016/j.lfs.2022.120996 -
Molecular Biology Reports Aug 2022Glioma is the most common malignant brain tumor in adults. The effects of conventional treatment regimens are still limited to prolonging the survival of patients....
INTRODUCTION
Glioma is the most common malignant brain tumor in adults. The effects of conventional treatment regimens are still limited to prolonging the survival of patients. Histone deacetylases (HDACs) are potential targets for tumor treatment. Pracinostat is a new type of HDAC inhibitor (HDACi) that has a significant antitumor effect on a variety of tumors. Thus, we aim to investigate the role of pracinostat in human glioma and explored its underlying mechanism.
METHODS
Cell viability, proliferation and apoptosis of human glioma cell lines were measured by Cell Counting kit 8 and flow cytometry. Pathway verification and protein interaction were determined by quantitative real-time polymerase chain reaction, Western blotting and immunofluorescence staining. Transwell technology was used to assess the migration and invasion of cells. Clinical significance of TIMP3, MMP9 and MMP2 in glioma was analyzed through The Cancer Genome Atlas (TCGA) database and the Genotype-Tissue Expression (GTEx) database.
RESULTS
Functionally, pracinostat not only inhibited proliferation and induced apoptosis but also inhibited migration and invasion in human glioma cell lines. Mechanistically, pracinostat increased the expression of TIMP3 and decreased the expression of MMP2, MMP9 and VEGF in human glioma cells in vitro and in vivo. In addition, pracinostat inhibited both the PI3K/Akt signaling pathway and the STAT3 pathway.
CONCLUSIONS
Our results strongly support the potential clinical use of pracinostat as a novel therapy for human glioma in the near future.
Topics: Adult; Apoptosis; Benzimidazoles; Cell Line, Tumor; Cell Movement; Cell Proliferation; Glioma; Histone Deacetylase Inhibitors; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Phenotype; Phosphatidylinositol 3-Kinases
PubMed: 35622308
DOI: 10.1007/s11033-022-07559-y