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.

Histone deacetylase inhibitors exert anti-tumor effects on human adherent and stem-like glioma cells 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis / Was, H.; Krol, S. K.; Rotili, D.; Mai, A.; Wojtas, B.; Kaminska, B.; Maleszewska, M.. - In: CLINICAL EPIGENETICS. - ISSN 1868-7083. - 11:1(2019), p. 11. [10.1186/s13148-018-0598-5]

Histone deacetylase inhibitors exert anti-tumor effects on human adherent and stem-like glioma cells 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis

Rotili D.;Mai A.;
2019

Abstract

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.
2019
Cell proliferation; Epigenetic drugs; Glioblastoma; Glioma stem cells; HDAC inhibitors; Histone deacetylase; Benzamides; Brain Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Methylation; Drug Screening Assays, Antitumor; Epigenesis, Genetic; Glioma; Histone Deacetylase 1; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Neoplastic Stem Cells; Pyrimidines; Spheroids, Cellular; Up-Regulation
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Histone deacetylase inhibitors exert anti-tumor effects on human adherent and stem-like glioma cells 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis / Was, H.; Krol, S. K.; Rotili, D.; Mai, A.; Wojtas, B.; Kaminska, B.; Maleszewska, M.. - In: CLINICAL EPIGENETICS. - ISSN 1868-7083. - 11:1(2019), p. 11. [10.1186/s13148-018-0598-5]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1355602
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