scholarly journals Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells

2006 ◽  
Vol 13 (4) ◽  
pp. 1237-1250 ◽  
Author(s):  
Viola Baradari ◽  
Alexander Huether ◽  
Michael Höpfner ◽  
Detlef Schuppan ◽  
Hans Scherübl
Keyword(s):  
Cell Lines ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Treatment Options ◽  
Combined Treatment ◽  
Hdac Inhibitors ◽  
Cyclin B1 ◽  
Hdac Inhibition ◽  
New Approach

Treatment options of advanced neuroendocrine tumors (NETs) are unsatisfactory. Hence, innovative therapeutic approaches are urgently needed. Inhibition of histone deacetylases (HDACs) is a promising new approach in cancer therapy. While several HDAC inhibitors have already entered clinical trials, the effect of HDAC inhibition on NET has not been investigated. Therefore, we evaluated the antineoplastic effects of three different HDAC inhibitors, trichostatin A (TSA), sodium butyrate (NaB), and MS-275, on growth and apoptosis of the gastrointestinal NET cell lines CM and BON. We could demonstrate that HDAC inhibition dose-dependently inhibited proliferation of both cell lines with IC50 values varying from the millimolar (NaB) to the micromolar (MS-275) and the nanomolar range (TSA). Moreover, HDAC inhibition potently induced apoptosis, which was accompanied by DNA-fragmentation, an up to 12-fold caspase-3 activation and downregulated Bcl-2 expression. Furthermore, HDAC inhibition resulted in cell cycle arrest at the G1–S-transition, which was associated with the suppression of cyclin D1 expression and induction of p21 and p27 expression. For BON cells, we observed an additional block in the G2/M phase, which was aligned with a downregulation of cyclin B1. In addition, combined treatment with MS-275 and somatostatin or the synthetic somatostatin analog octreotide was evaluated. Neither somatostatin nor its stable analog octreotide augmented the antiproliferative effect of MS-275 in NET cells. To conclude, our data show that HDAC inhibition is a promising new approach in the treatment of NET disease, which should be evaluated in clinical studies.

scholarly journals DNA and histone deacetylases as targets for neuroblastoma treatment

2010 ◽  
Vol 3 (2) ◽  
pp. 47-52 ◽  
Author(s):  
Marie Stiborová ◽  
Jitka Poljaková ◽  
Tomáš Eckschlager ◽  
Rene Kizek ◽  
Eva Frei
Keyword(s):  
Cell Lines ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Treatment Options ◽  
Neuroblastoma Cell ◽  
Proper Function ◽  
Antitumor Action ◽  
New Therapies ◽  
Neuroblastoma Cell Lines

DNA and histone deacetylases as targets for neuroblastoma treatmentNeuroblastoma, a tumor of the peripheral sympathetic nervous system, is the most frequent solid extra cranial tumor in children and is a major cause of death from neoplasia in infancy. Still little improvement in therapeutic options has been made, requiring a need for the development of new therapies. In our laboratory, we address still unsettled questions, which of mechanisms of action of DNA-damaging drugs both currently use for treatment of human neuroblastomas (doxorubicin, cis-platin, cyclophosphamide and etoposide) and another anticancer agent decreasing growth of neuroblastomasin vitro, ellipticine, are predominant mechanism(s) responsible for their antitumor action in neuroblastoma cell linesin vitro.Because hypoxia frequently occurs in tumors and strongly correlates with advanced disease and poor outcome caused by chemoresistance, the effects of hypoxia on efficiencies and mechanisms of actions of these drugs in neuroblastomas are also investigated. Since the epigenetic structure of DNA and its lesions play a role in the origin of human neuroblastomas, pharmaceutical manipulation of the epigenome may offer other treatment options also for neuroblastomas. Therefore, the effects of histone deacetylase inhibitors on growth of neuroblastoma and combination of these compounds with doxorubicin, cis-platin, etoposide and ellipticine as well as mechanisms of such effects in human neuroblastona cell linesin vitroare also investigated. Such a study will increase our knowledge to explain the proper function of these drugs on the molecular level, which should be utilized for the development of new therapies for neuroblastomas.

Histone deacetylase inhibitors suppress IFNα-induced up-regulation of promyelocytic leukemia protein

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1373-1380 ◽  
Author(s):  
Jana Vlasáková ◽  
Zora Nováková ◽  
Lenka Rossmeislová ◽  
Michal Kahle ◽  
Pavel Hozák ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Eukaryotic Cell ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Interferon Α

Abstract Promyelocytic leukemia nuclear bodies (PML NBs), the structural domains of the eukaryotic cell nucleus, play a role in cancer and apoptosis, and their involvement in antiviral mechanisms mediated by interferons (IFNs) is proposed. IFNs dramatically increase the transcription of the PML gene. In this study, we have shown that the response of 2 structural PML NB components, PML and Sp100, to interferon-α (IFNα) was suppressed in cells simultaneously treated with histone deacetylase (HDAC) inhibitors (trichostatin A, sodium butyrate, MS-275, SAHA, and valproic acid). Trichostatin A (TSA) blocked the increase of PML NB number and suppressed up-regulation of PML mRNA and protein levels in several human cell lines and in normal diploid skin fibroblasts. Moreover, IFNα induction of IRF-1 was also inhibited by TSA, although incompletely. Analysis of cellular fractions did not show any defects in cytoplasmic-nuclear transport of STAT2, a component of transcription factor ISGF3 responsible for IFNα/β-dependent gene transcription. Moreover, chromatin immunoprecipitation showed that after IFNα stimulation STAT2 binds to ISRE element of PML promoter even in the presence of TSA and thus excluded STAT2-dependent mechanism of TSA effect. These results indicate that the action of histone deacetylases is necessary for the full transcriptional activation of IFNα-stimulated genes.

scholarly journals Histone Deacetylase Inhibitors Modify Pancreatic Cell Fate Determination and Amplify Endocrine Progenitors

2008 ◽  
Vol 28 (20) ◽  
pp. 6373-6383 ◽  
Author(s):  
Cécile Haumaitre ◽  
Olivia Lenoir ◽  
Raphaël Scharfmann
Keyword(s):  
Cell Fate ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Developmentally Regulated ◽  
Pancreatic Cell ◽  
Endocrine Differentiation ◽  
Potential Applications ◽  
Endocrine Progenitors

ABSTRACT During pancreas development, transcription factors play critical roles in exocrine and endocrine differentiation. Transcriptional regulation in eukaryotes occurs within chromatin and is influenced by posttranslational histone modifications (e.g., acetylation) involving histone deacetylases (HDACs). Here, we show that HDAC expression and activity are developmentally regulated in the embryonic rat pancreas. We discovered that pancreatic treatment with different HDAC inhibitors (HDACi) modified the timing and determination of pancreatic cell fate. HDACi modified the exocrine lineage via abolition and enhancement of acinar and ductal differentiation, respectively. Importantly, HDACi treatment promoted the NGN3 proendocrine lineage, leading to an increased pool of endocrine progenitors and modified endocrine subtype lineage choices. Interestingly, treatments with trichostatin A and sodium butyrate, two inhibitors of both class I and class II HDACs, enhanced the pool of β cells. These results highlight the roles of HDACs at key points in exocrine and endocrine differentiation. They show the powerful use of HDACi to switch pancreatic cell determination and amplify specific cellular subtypes, with potential applications in cell replacement therapies in diabetes.

Novel Conjugated Quinazolinone-Based Hydroxamic Acids: Design, Synthesis and Biological Evaluation

2020 ◽  
Vol 16 ◽  
Author(s):  
Tran Khac Vu ◽  
Nguyen Thi Thanh ◽  
Nguyen Van Minh ◽  
Nguyen Huong Linh ◽  
Nguyen Thi Phương Thao ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cell Lines ◽  
Cancer Cell ◽  
Hdac Inhibitors ◽  
Cancer Cell Lines ◽  
Hydroxamic Acids ◽  
Biological Evaluation ◽  
Hdac Inhibition ◽  
Ic50 Value ◽  
Mcf 7

Background: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development. Histone deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat. Aims: This study aims at developing novel HDAC inhibitors bearing conjugated quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. Method: A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin-4(3H)- ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain more insight into the structure-activity. relationships. Results: It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds 15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with IC50 value of 1.86 µM, and HDAC inhibition with IC50 value of 6.36 µM. Docking experiments on HDAC2 isozyme showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward SKLu-1than MCF-7 and HepG-2. Conclusion: The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.

scholarly journals Histone Deacetylase Inhibitors and Microtubule Inhibitors Induce Apoptosis in Feline Luminal Mammary Carcinoma Cells

Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 502
Author(s):  
Filipe Almeida ◽  
Andreia Gameiro ◽  
Jorge Correia ◽  
Fernando Ferreira
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Line ◽  
Cell Lines ◽  
Mammary Carcinoma ◽  
Human Breast Cancer ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Human Breast ◽  
Antitumor Effects

Feline mammary carcinoma (FMC) is the third most common type of neoplasia in cats, sharing similar epidemiological features with human breast cancer. In humans, histone deacetylases (HDACs) play an important role in the regulation of gene expression, with HDAC inhibitors (HDACis) disrupting gene expression and leading to cell death. In parallel, microtubules inhibitors (MTIs) interfere with the polymerization of microtubules, leading to cell cycle arrest and apoptosis. Although HDACis and MTIs are used in human cancer patients, in cats, data is scarce. In this study, we evaluated the antitumor properties of six HDACis (CI-994, panobinostat, SAHA, SBHA, scriptaid, and trichostatin A) and four MTIs (colchicine, nocodazole, paclitaxel, and vinblastine) using three FMC cell lines (CAT-MT, FMCp, and FMCm), and compared with the human breast cancer cell line (SK-BR-3). HDACis and MTIs exhibited dose-dependent antitumor effects in FMC cell lines, and for all inhibitors, the IC50 values were determined, with one feline cell line showing reduced susceptibility (FMCm). Immunoblot analysis confirmed an increase in the acetylation status of core histone protein HDAC3 and flow cytometry showed that HDACis and MTIs lead to cellular apoptosis. Overall, our study uncovers HDACis and MTIs as promising anti-cancer agents to treat FMCs.

Histone deacetylase inhibitors and their potential role in inflammatory bowel diseases

2011 ◽  
Vol 39 (4) ◽  
pp. 1092-1095 ◽  
Author(s):  
Alexander J.P. Edwards ◽  
Sylvia L.F. Pender
Keyword(s):  
Gene Transcription ◽  
Inflammatory Bowel Diseases ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
T Regulatory Cells ◽  
Hdac Inhibitors ◽  
Novel Treatments ◽  
Bowel Diseases ◽  
Normal Gene ◽  
Inflammatory Bowel

IBDs (inflammatory bowel diseases) are lifelong manifestations that significantly impair the quality of life of those who suffer from them. Although many therapies are now available, including immunomodulatory drugs such as Infliximab which have efficacy in IBD, not all patients respond and some patients generate autoantibodies against these drugs. Hence the search for novel treatments is ongoing. HDACs (histone deacetylases) are responsible for condensation of chromatin in the nucleus of cells and inhibition of gene transcription and are often dysregulated during cancer. HDAC inhibitors allow normal gene transcription to be restored and provide attractive therapeutic options, as they have been shown to be anti-inflammatory and anti-proliferative in cancer. Indeed, two HDAC inhibitors have been recently approved for the treatment of cutaneous T-cell lymphoma in the U.S.A. Recent research using animal models has shown that HDAC inhibitors may have a beneficial effect in colitis by boosting levels of Foxp3+ (forkhead box P3+) T-regulatory cells that dampen inflammation. In the present paper, we outline the background to IBD, HDACs and their inhibitors as well as discussing their current use in models of IBD.

Trichostatin A sensitivity signature across hematological cell lines.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19521-e19521
Author(s):  
Bartlomiej Przychodzen
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
B Lymphocyte ◽  
Trichostatin A ◽  
Expression Profiles ◽  
Cell Maturation ◽  
B Cell Maturation

e19521 Background: Histone deacetylase inhibitors (HDACi) are small molecules that increase acetylation of lysine residues by blocking histone deactylases. These anticancer agents affect epigenetic and non-epigenetic gene expression resulting in cell cycle arrest of cancer cells. Furthermore HDACi can enhance its anti-tumor effects via the pharmacologic modulation of macrophage. Some HDACi’s such as Trichostatin A (TSA) can also affected the tumor immune microenvironment by suppressing the activity of infiltrating macrophages and inhibiting myeloid-derived suppressor cell recruiement (Li et al.,). Methods: We conducted a high throughput screen comparing gene expression profiles in known hematological cell lines to identify transcriptional signatures associated with TSA sensitivity obtained from GDSC. Results: We selected genes that showed at least 2fold expression difference and were statistically significant (p < 0.05). We identified 49 genes that were upregulated and 85 that were downregulated. The most significant results include multiple genes known to be correlated with the B-cell maturation process. We found that CD24 a small GPI linked glycoprotein expressed at the surface of most B lymphocyte precursors, neutrophils, epithelial cells and frequently found to be highly expressed in various hematological and solid neoplasms, was up/downregulatred by XX. Interestingly, CD24 plays a role in the activation and differentiation of the cells as bone marrow samples lacking CD24 resulted in decreased numbers of both pre-B and immature B-cell populations. We also found that IKZF2, a transcription factor regulating lymphocyte development and queiesence and which is frequently deleted in hypodiploid B-ALLs. This result could revelent as other reports suggest a role of IKZF2 as a tumor suppressor with a central role regulating the balance of self-renewal and differentiation in leukemic stem cells. Conclusions: Our study identified transcriptional profiles which suggest that TSA sensitivity could be related to B cell maturation. Further experiments warrant replication of these findings which could prove useful in creating optimal, TSA-based treatments acting either as potent single agents or in combination enhancing anti-tumor effects of immunotherapies.

NEW AND EMERGING HDAC INHIBITORS FOR THE TREATMENT OF DISEASES

INDIAN DRUGS ◽  
2014 ◽  
Vol 51 (06) ◽  
pp. 5-15
Author(s):  
S.S Mahajan ◽  
◽  
A Chavan
Keyword(s):  
Lupus Erythematosus ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Cell Lymphoma ◽  
Human Cancer ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
New Strategy ◽  
Us Fda

Histone deacetylases (HDACs) are critical in regulating gene expression and transcription. They also play a fundamental role in regulating cellular activities such as cell proliferation, survival and differentiation. Inhibition of histone deacetylases has generated many fascinating results including a new strategy in human cancer therapy. Suberoylanilide hydroxamic acid (SAHA) and romidepsin are the two drugs approved by US FDA for the treatment of cutaneous T-cell lymphoma. The HDAC inhibitors (HDACIs) like trichostatin A and SAHA are also emerging as new promising drugs for various conditions like rheumatoid arthritis, colitis, systemic lupus erythematosus and CNS disorders. This review, along with chemical classification of HDACIs, emphasizes on the therapeutic potential of various HDACIs against different diseases.

scholarly journals Histone Deacetylase Inhibitors Down-Regulate bcl-2 Expression and Induce Apoptosis in t(14;18) Lymphomas

2005 ◽  
Vol 25 (5) ◽  
pp. 1608-1619 ◽  
Author(s):  
Hong Duan ◽  
Caroline A. Heckman ◽  
Linda M. Boxer
Keyword(s):  
Cell Cycle ◽  
Histone Deacetylase ◽  
Chromatin Immunoprecipitation ◽  
Histone Deacetylase Inhibitors ◽  
Antitumor Agents ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Transcriptional Level ◽  
Cycle Arrest ◽  
Induced Apoptosis

ABSTRACT Histone deacetylase (HDAC) inhibitors are promising antitumor agents, but they have not been extensively explored in B-cell lymphomas. Many of these lymphomas have the t(14;18) translocation, which results in increased bcl-2 expression and resistance to apoptosis. In this study, we examined the effects of two structurally different HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), on the cell cycle, apoptosis, and bcl-2 expression in t(14;18) lymphoma cells. We found that in addition to potent cell cycle arrest, TSA and NaB also dramatically induced apoptosis and down-regulated bcl-2 expression, and overexpression of bcl-2 inhibited TSA-induced apoptosis. The repression of bcl-2 by TSA occurred at the transcriptional level. Western blot analysis and quantitative chromatin immunoprecipitation (ChIP) assay showed that even though HDAC inhibitors increased overall acetylation of histones, localized histone H3 deacetylation occurred at both bcl-2 promoters. TSA treatment increased the acetylation of the transcription factors Sp1 and C/EBPα and decreased their binding as well as the binding of CBP and HDAC2 to the bcl-2 promoters. Mutation of Sp1 and C/EBPα binding sites reduced the TSA-induced repression of bcl-2 promoter activity. This study provides a mechanistic rationale for the use of HDAC inhibitors in the treatment of human t(14;18) lymphomas.

scholarly journals Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 717 ◽  
Author(s):  
Na Zhao ◽  
Feifei Yang ◽  
Lina Han ◽  
Yuhua Qu ◽  
Di Ge ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Human Cancer ◽  
Immunoblot Analysis ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Human Cancer Cell Lines

Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds 6 and 7 displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36–2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, 13a and 13c arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound 13c.

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