scholarly journals Histone Deacetylase Inhibitors Enhance Cell Killing and Block Interferon-Beta Synthesis Elicited by Infection with an Oncolytic Parainfluenza Virus

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 431 ◽  
Author(s):  
Candace R. Fox ◽  
Griffith D. Parks
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Cancer Cell ◽  
Histone Deacetylase Inhibitors ◽  
Interferon Beta ◽  
Hdac Inhibitors ◽  
Chemotherapeutic Agents ◽  
Cell Killing ◽  
Parainfluenza Virus

Previous results have shown that infection with the cytoplasmic-replicating parainfluenza virus 5 mutant P/V-CPI- sensitizes cells to DNA damaging agents, resulting in the enhanced killing of airway cancer cells. Here, we have tested the hypothesis that histone deacetylase (HDAC) inhibitors can also act with P/V-CPI- infection to enhance cancer cell killing. Using human small cell lung cancer and laryngeal cancer cell lines, 10 HDAC inhibitors were tested for their effect on viability of P/V-CPI- infected cells. HDAC inhibitors such as scriptaid enhanced caspase-3/7, -8 and -9 activity induced by P/V-CPI- and overall cell toxicity. Scriptaid-mediated enhanced killing was eliminated in lung cancer cells that were engineered to express a protein which sequesters double stranded RNA. Scriptaid also enhanced cancer cell killing by two other negative strand RNA viruses – the La Crosse virus and vesicular stomatitis virus. Scriptaid treatment enhanced the spread of the P/V-CPI- virus through a population of cancer cells, and suppressed interferon-beta induction through blocking phosphorylation and nuclear translocation of Interferon Regulatory Factor 3 (IRF-3). Taken together, these data support a role for combinations of a cytoplasmic-replicating RNA virus such as the P/V-CPI- mutant along with chemotherapeutic agents.

Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy) methyl)-N-hydroxybenzamides/propenamides as Histone Deacetylase Inhibitors and Antitumor Agents

2019 ◽  
Vol 19 (4) ◽  
pp. 546-556
Author(s):  
Duong T. Anh ◽  
Nguyen T. Thuan ◽  
Pham-The Hai ◽  
Le-Thi-Thu Huong ◽  
Nguyen T.K. Yen ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Antitumor Agents ◽  
Human Cancer ◽  
Hdac Inhibitors ◽  
Cancer Cell Lines ◽  
Inhibitory Potency

Background: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer 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 givinostat (ITF2357) and belinostat (PXD-101). Aims: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines. Methods: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. Results: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities. Conclusions: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.

scholarly journals Energy Metabolism in H460 Lung Cancer Cells: Effects of Histone Deacetylase Inhibitors

PLoS ONE ◽  
2011 ◽  
Vol 6 (7) ◽  
pp. e22264 ◽  
Author(s):  
Nívea Dias Amoêdo ◽  
Mariana Figueiredo Rodrigues ◽  
Paula Pezzuto ◽  
Antonio Galina ◽  
Rodrigo Madeiro da Costa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Energy Metabolism ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Lung Cancer Cells

scholarly journals Histone Deacetylase Inhibitors Sensitize Lung Cancer Cells to Hyperthermia: Involvement of Ku70/SirT-1 in Thermo-Protection

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94213 ◽  
Author(s):  
Mohamed K. Hassan ◽  
Hidemichi Watari ◽  
Alaa-eldin Salah-eldin ◽  
Ahmed S. Sultan ◽  
Zainab Mohamed ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Lung Cancer Cells

Design, Synthesis and Biological Evaluation of Novel N-hydroxyheptanamides Incorporating 6-hydroxy-2-methylquinazolin-4(3H)-ones as Histone Deacetylase Inhibitors and Cytotoxic Agents

2019 ◽  
Vol 19 (12) ◽  
pp. 1543-1557
Author(s):  
Nguyen V. Minh ◽  
Nguyen T. Thanh ◽  
Hoang T. Lien ◽  
Dinh T.P. Anh ◽  
Ho D. Cuong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Discovery ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Hdac Inhibitors ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
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 worldwide, and 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 quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. Methods: A series of novel N-hydroxyheptanamides incorporating 6-hydroxy-2 methylquinazolin-4(3H)-ones (14a-m) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2 (liver cancer), MCF-7 (breast cancer) and SKLu-1 (lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. ADME-T predictions for selected compounds were also performed to predict some important features contributing to the absorption profile of the present hydroxamic derivatives. Results: It was found that the N-hydroxyheptanamide 14i and 14j were the most potent, both in terms of HDAC inhibition and cytotoxicity. These compounds displayed up to 21-71-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in terms of cytotoxicity, and strong inhibition against the whole cell HDAC enzymes with IC50 values of 7.07-9.24μM. Docking experiments on HDAC2 isozyme using Autodock Vina showed all compounds bound to HDAC2 with relatively higher affinities (from -7.02 to -11.23 kcal/mol) compared to SAHA (-7.4 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward breast cancer cells (MCF-7) than liver (HepG2), and lung (SKLu-1) cancer cells.

scholarly journals Inhibition of Histone Deacetylase Activity Promotes Invasion of Human Cancer Cells through Activation of Urokinase Plasminogen Activator

2007 ◽  
Vol 282 (49) ◽  
pp. 35594-35603 ◽  
Author(s):  
Sai Murali Krishna Pulukuri ◽  
Bharathi Gorantla ◽  
Jasti S. Rao
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Plasminogen Activator ◽  
Histone Deacetylase ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Human Cancer ◽  
Hdac Inhibitors ◽  
Cancer Cell Invasion ◽  
Human Cancer Cells

Histone acetylation plays an important role in chromatin remodeling and gene expression. The molecular mechanisms involved in differential regulation of urokinase plasminogen activator (uPA) gene expression are not fully understood. In this study, we investigated whether histone deacetylation was involved in repression of uPA expression in human cancer cells. Induction of uPA expression by histone deacetylase (HDAC) inhibitors trichostatin A (TSA), sodium butyrate, and scriptaid was observed in all three different types of human cancer cells examined. Chromatin immunoprecipitation assays showed that the induction of uPA expression by TSA was accompanied by a remarkable increase of acetylation of histones H3 and H4, which are associated with the uPA promoter region in human cancer cells. These results were further substantiated by the findings of a restriction enzyme accessibility assay and TSA-stimulated uPA promoter activity through the inhibition of HDAC activity. In vitro Matrigel invasion assays showed that induction of uPA expression by HDAC inhibitors in human cancer cells resulted in a significant increase of cancer cell invasion. Furthermore, HDAC1 knockdown by small interference RNA stimulated uPA expression and cancer cell invasion. In conclusion, this study demonstrates the important role of histone modifications in regulating uPA gene expression and raises a possibility that the use of HDAC inhibitors in patients as cancer therapy may paradoxically establish metastasis through up-regulation or reactivation of uPA.

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