Histone deacetylase inhibitors exert anti-tumor effects on human adherent and stem-like glioma cells.
Benzamides
/ pharmacology
Brain Neoplasms
/ drug therapy
Cell Adhesion
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
DNA Methylation
/ drug effects
Drug Screening Assays, Antitumor
Epigenesis, Genetic
/ drug effects
Glioma
/ drug therapy
Histone Deacetylase 1
/ genetics
Histone Deacetylase 2
/ genetics
Histone Deacetylase Inhibitors
/ pharmacology
Histone Deacetylases
/ genetics
Humans
Neoplastic Stem Cells
/ cytology
Pyrimidines
/ pharmacology
Spheroids, Cellular
/ cytology
Up-Regulation
/ drug effects
Cell proliferation
Epigenetic drugs
Glioblastoma
Glioma stem cells
HDAC inhibitors
Histone deacetylase
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
17 01 2019
17 01 2019
Historique:
received:
01
08
2018
accepted:
17
12
2018
entrez:
19
1
2019
pubmed:
19
1
2019
medline:
21
8
2019
Statut:
epublish
Résumé
The diagnosis of glioblastoma (GBM), a most aggressive primary brain tumor with a median survival of 14.6 months, carries a dismal prognosis. GBMs are characterized by numerous genetic and epigenetic alterations, affecting patient survival and treatment response. Epigenetic mechanisms are deregulated in GBM as a result of aberrant expression/activity of epigenetic enzymes, including histone deacetylases (HDAC) which remove acetyl groups from histones regulating chromatin accessibility. Nevertheless, the impact of class/isoform-selective HDAC inhibitors (HDACi) on glioma cells, including glioma stem cells, had not been systematically determined. Comprehensive analysis of the public TCGA dataset revealed the increased expression of HDAC 1, 2, 3, and 7 in malignant gliomas. Knockdown of HDAC 1 and 2 in human GBM cells significantly decreased cell proliferation. We tested the activity of 2 new and 3 previously described HDACi with different class/isoform selectivity on human GBM cells. All tested compounds exerted antiproliferative properties on glioma cells. However, the HDACi 1 and 4 blocked proliferation of glioblastoma cells leading to G2/M growth arrest without affecting astrocyte survival. Moreover, 1 and 4 at low micromolar concentrations displayed cytotoxic and antiproliferative effects on sphere cultures enriched in glioma stem cells. We identified two selective HDAC inhibitors that blocked proliferation of glioblastoma cells, but did not affect astrocyte survival. These new and highly effective inhibitors should be considered as promising candidates for further investigation in preclinical GBM models.
Sections du résumé
BACKGROUND
The diagnosis of glioblastoma (GBM), a most aggressive primary brain tumor with a median survival of 14.6 months, carries a dismal prognosis. GBMs are characterized by numerous genetic and epigenetic alterations, affecting patient survival and treatment response. Epigenetic mechanisms are deregulated in GBM as a result of aberrant expression/activity of epigenetic enzymes, including histone deacetylases (HDAC) which remove acetyl groups from histones regulating chromatin accessibility. Nevertheless, the impact of class/isoform-selective HDAC inhibitors (HDACi) on glioma cells, including glioma stem cells, had not been systematically determined.
RESULTS
Comprehensive analysis of the public TCGA dataset revealed the increased expression of HDAC 1, 2, 3, and 7 in malignant gliomas. Knockdown of HDAC 1 and 2 in human GBM cells significantly decreased cell proliferation. We tested the activity of 2 new and 3 previously described HDACi with different class/isoform selectivity on human GBM cells. All tested compounds exerted antiproliferative properties on glioma cells. However, the HDACi 1 and 4 blocked proliferation of glioblastoma cells leading to G2/M growth arrest without affecting astrocyte survival. Moreover, 1 and 4 at low micromolar concentrations displayed cytotoxic and antiproliferative effects on sphere cultures enriched in glioma stem cells.
CONCLUSIONS
We identified two selective HDAC inhibitors that blocked proliferation of glioblastoma cells, but did not affect astrocyte survival. These new and highly effective inhibitors should be considered as promising candidates for further investigation in preclinical GBM models.
Identifiants
pubmed: 30654849
doi: 10.1186/s13148-018-0598-5
pii: 10.1186/s13148-018-0598-5
pmc: PMC6337817
doi:
Substances chimiques
Benzamides
0
Histone Deacetylase Inhibitors
0
Pyrimidines
0
mocetinostat
A6GWB8T96J
HDAC1 protein, human
EC 3.5.1.98
HDAC2 protein, human
EC 3.5.1.98
HDAC7 protein, human
EC 3.5.1.98
Histone Deacetylase 1
EC 3.5.1.98
Histone Deacetylase 2
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
histone deacetylase 3
EC 3.5.1.98
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
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