scholarly journals A Tiny Change Makes a Big Difference in the Anti-Parasitic Activities of an HDAC Inhibitor

2019 ◽  
Vol 20 (12) ◽  
pp. 2973 ◽  
Author(s):  
Corinne Loeuillet ◽  
Bastien Touquet ◽  
Jean François Guichou ◽  
Gilles Labesse ◽  
Denis Sereno
Keyword(s):  
Toxoplasma Gondii ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
In Silico ◽  
Histone Deacetylase Inhibitor ◽  
Type Ii ◽  
Deacetylase Inhibitor ◽  
In Silico Modeling ◽  
High Conservation ◽  
Methyl Benzene

We previously synthesized an hydroxamate derivative (N-hydroxy-4-[2-(3- methoxyphenyl)acetamido]benzamide) named 363 with potent anti-Toxoplasma gondii activity and histone deacetylase inhibitor (HDACi) effects. Here we show that 1-N-hydroxy-4-N- [(2-methoxyphenyl)methyl]benzene-1,4-dicarboxamide, a 363 isomer, does not have antiparasitic potency and has a 13-fold decrease in HDACi activity. The in silico modeling of T. gondii HDACs of the type II strain discloses identity varying from 25% to 62% on more than 250 residues for S8EP32_TOXG and A0A125YPH4_TOXGM. We observed a high conservation degree with the human HDAC2 (53% and 64% identity, respectively) and a moderate one with the human HDAC8 (30–40%). Two other TgHDACs, S8F6L4_TOXGM and S8GEI3_TOXGM, were identified as displaying a higher similarity with some bacterial orthologs (~35%) than with the human enzymes (~25%). The docking in parallel of the two compounds on the models generated allowed us to gain insights on the docking of these hydroxamate derivatives that guide their specificity and potency against T. gondii histone deacetylase. This information would constitute the rationale from which more specific derivatives can be synthetized.

scholarly journals Givinostat, a type II histone deacetylase inhibitor, induces potent caspase-dependent apoptosis in human lymphoblastic leukemia

2016 ◽  
Vol 7 (9-10) ◽  
pp. 292-300 ◽  
Author(s):  
Ying Li ◽  
Kevin Zhao ◽  
Chenjiao Yao ◽  
Samir Kahwash ◽  
Yan Tang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Type Ii ◽  
Deacetylase Inhibitor

scholarly journals Histone Deacetylase Inhibitor Depsipeptide Activates Silenced Genes through Decreasing both CpG and H3K9 Methylation on the Promoter

2008 ◽  
Vol 28 (10) ◽  
pp. 3219-3235 ◽  
Author(s):  
Li-Peng Wu ◽  
Xi Wang ◽  
Lian Li ◽  
Ying Zhao ◽  
Shaoli Lu ◽  
...  
Keyword(s):  
Cell Line ◽  
Histone Deacetylase ◽  
Cancer Cell ◽  
Hdac Inhibitor ◽  
Histone Deacetylase Inhibitor ◽  
Cancer Cell Line ◽  
Dna Demethylation ◽  
Human Lung Cancer ◽  
Histone Methyltransferases ◽  
Deacetylase Inhibitor

ABSTRACT Histone deacetylase inhibitor (HDACi) has been shown to demethylate the mammalian genome, which further strengthens the concept that DNA methylation and histone modifications interact in regulation of gene expression. Here, we report that an HDAC inhibitor, depsipeptide, exhibited significant demethylating activity on the promoters of several genes, including p16, SALL3, and GATA4 in human lung cancer cell lines H719 and H23, colon cancer cell line HT-29, and pancreatic cancer cell line PANC1. Although expression of DNA methyltransferase 1 (DNMT1) was not affected by depsipeptide, a decrease in binding of DNMT1 to the promoter of these genes played a dominant role in depsipeptide-induced demethylation and reactivation. Depsipeptide also suppressed expression of histone methyltransferases G9A and SUV39H1, which in turn resulted in a decrease of di- and trimethylated H3K9 around these genes' promoter. Furthermore, both loading of heterochromatin-associated protein 1 (HP1α and HP1β) to methylated H3K9 and binding of DNMT1 to these genes' promoter were significantly reduced in depsipeptide-treated cells. Similar DNA demethylation was induced by another HDAC inhibitor, apicidin, but not by trichostatin A. Our data describe a novel mechanism of HDACi-mediated DNA demethylation via suppression of histone methyltransferases and reduced recruitment of HP1 and DNMT1 to the genes' promoter.

Histone Deacetylase Inhibitor, Panobinostat Exerts Anti-proliferative Effect with Partial Normalization from Aberrant Epigenetic States on Granulosa Cell Tumor Cell Lines

2021 ◽  
Author(s):  
Yukiko Hazama ◽  
Takayuki Tsujioka ◽  
Arisu Sakamoto ◽  
Yuka Miyaji ◽  
Akira Kitanaka ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Histone Deacetylase ◽  
Granulosa Cell ◽  
Cell Lines ◽  
Hdac Inhibitor ◽  
Histone Deacetylase Inhibitor ◽  
Related Gene ◽  
Gene Set ◽  
Proliferative Effect ◽  
Deacetylase Inhibitor

Abstract The prognosis of the patients with inoperable or advanced granulosa cell tumors (GCTs) is still poor, and therefore it is important to establish a novel treatment strategy. Here we investigated the in vitro effects of a histone deacetylase inhibitor, panobinostat (PS) on two GCT cell lines (KGN and COV434). GCT cell lines were found to be susceptible to PS treatment and it inhibited cell growth mainly by apoptosis. In cell cycle analysis, PS reduced only the ratio of S phase in GCT cell lines. Combined treatment of PS with a deubiquitinases inhibitor, VLX1570 exerted an additive anti-proliferative effect on KGN and COV434. The gene set enrichment analysis revealed that PS treatment suppressed DNA replication- or cell cycle-related gene expression which led to chemotherapeutic cell death and in addition, this treatment induced activation of the gene set of adherens junction towards a normalized direction as well as activation of neuron-related gene sets that might imply unexpected differentiation potential due to epigenetic modification by a HDAC inhibitor in KGN cells. In the present study, we indicate a basis of a novel therapeutic availability of a HDAC inhibitor for the treatment of GCTs and further investigations will be warranted.

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