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Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres

Glioblastoma stem-like cells (GSLCs) in glioblastoma limit effective treatment and promote therapeutic resistance and tumor recurrence. Using a combined radiation and drug-screening platform, we tested the combination of a histone deacetylase inhibitor (HDACi) and MAPK/ERK kinase inhibitor (MEKi) wi...

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Autores principales: Essien, Eno I., Hofer, Thomas P., Atkinson, Michael J., Anastasov, Nataša
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909581/
https://www.ncbi.nlm.nih.gov/pubmed/35269397
http://dx.doi.org/10.3390/cells11050775
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author Essien, Eno I.
Hofer, Thomas P.
Atkinson, Michael J.
Anastasov, Nataša
author_facet Essien, Eno I.
Hofer, Thomas P.
Atkinson, Michael J.
Anastasov, Nataša
author_sort Essien, Eno I.
collection PubMed
description Glioblastoma stem-like cells (GSLCs) in glioblastoma limit effective treatment and promote therapeutic resistance and tumor recurrence. Using a combined radiation and drug-screening platform, we tested the combination of a histone deacetylase inhibitor (HDACi) and MAPK/ERK kinase inhibitor (MEKi) with radiation to predict the efficacy against GSLCs. To mimic a stem-like phenotype, glioblastoma-derived spheres were used and treated with a combination of HDACi (MS-275) and MEKi (TAK-733 or trametinib) with 4 Gy irradiation. The sphere-forming ability after the combined radiochemotherapy was investigated using a sphere formation assay, while the expression levels of the GSLC markers (CD44, Nestin and SOX2) after treatment were analyzed using Western blotting and flow cytometry. The combined radiochemotherapy treatment inhibited the sphere formation in both glioblastoma-derived spheres, decreased the expression of the GSLC markers in a cell-line dependent manner and increased the dead cell population. Finally, we showed that the combined treatment with radiation was more effective at reducing the GSLC markers compared to the standard treatment of temozolomide and radiation. These results suggest that combining HDAC and MEK inhibition with radiation may offer a new strategy to improve the treatment of glioblastoma.
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spelling pubmed-89095812022-03-11 Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres Essien, Eno I. Hofer, Thomas P. Atkinson, Michael J. Anastasov, Nataša Cells Article Glioblastoma stem-like cells (GSLCs) in glioblastoma limit effective treatment and promote therapeutic resistance and tumor recurrence. Using a combined radiation and drug-screening platform, we tested the combination of a histone deacetylase inhibitor (HDACi) and MAPK/ERK kinase inhibitor (MEKi) with radiation to predict the efficacy against GSLCs. To mimic a stem-like phenotype, glioblastoma-derived spheres were used and treated with a combination of HDACi (MS-275) and MEKi (TAK-733 or trametinib) with 4 Gy irradiation. The sphere-forming ability after the combined radiochemotherapy was investigated using a sphere formation assay, while the expression levels of the GSLC markers (CD44, Nestin and SOX2) after treatment were analyzed using Western blotting and flow cytometry. The combined radiochemotherapy treatment inhibited the sphere formation in both glioblastoma-derived spheres, decreased the expression of the GSLC markers in a cell-line dependent manner and increased the dead cell population. Finally, we showed that the combined treatment with radiation was more effective at reducing the GSLC markers compared to the standard treatment of temozolomide and radiation. These results suggest that combining HDAC and MEK inhibition with radiation may offer a new strategy to improve the treatment of glioblastoma. MDPI 2022-02-23 /pmc/articles/PMC8909581/ /pubmed/35269397 http://dx.doi.org/10.3390/cells11050775 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Essien, Eno I.
Hofer, Thomas P.
Atkinson, Michael J.
Anastasov, Nataša
Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres
title Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres
title_full Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres
title_fullStr Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres
title_full_unstemmed Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres
title_short Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres
title_sort combining hdac and mek inhibitors with radiation against glioblastoma-derived spheres
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909581/
https://www.ncbi.nlm.nih.gov/pubmed/35269397
http://dx.doi.org/10.3390/cells11050775
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