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The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells

Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers in cultures with Bcl-XL over-expression. We study the efficacy of SAHA/RTx and LBH589/RTx when manipulating Bcl-2 family proteins using the Bcl-2 inhibitor Obatoclax in patient-derived glioblastoma stem-l...

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Autores principales: Berghauser Pont, Lotte M.E., Spoor, Jochem K.H., Venkatesan, Subramanian, Swagemakers, Sigrid, Kloezeman, Jenneke J., Dirven, Clemens M.F., van der Spek, Peter J., Lamfers, Martine L.M., Leenstra, Sieger
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279441/
https://www.ncbi.nlm.nih.gov/pubmed/25568669
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author Berghauser Pont, Lotte M.E.
Spoor, Jochem K.H.
Venkatesan, Subramanian
Swagemakers, Sigrid
Kloezeman, Jenneke J.
Dirven, Clemens M.F.
van der Spek, Peter J.
Lamfers, Martine L.M.
Leenstra, Sieger
author_facet Berghauser Pont, Lotte M.E.
Spoor, Jochem K.H.
Venkatesan, Subramanian
Swagemakers, Sigrid
Kloezeman, Jenneke J.
Dirven, Clemens M.F.
van der Spek, Peter J.
Lamfers, Martine L.M.
Leenstra, Sieger
author_sort Berghauser Pont, Lotte M.E.
collection PubMed
description Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers in cultures with Bcl-XL over-expression. We study the efficacy of SAHA/RTx and LBH589/RTx when manipulating Bcl-2 family proteins using the Bcl-2 inhibitor Obatoclax in patient-derived glioblastoma stem-like cell (GSC) cultures. GSC cultures in general have a deletion in phosphatase and tensin homolog (PTEN). Synergy was determined by the Chou Talalay method. The effects on apoptosis and autophagy were studied by measuring caspase-3/7, Bcl-XL, Mcl-1 and LC3BI/II proteins. The relation between treatment response and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, recurrence and gene expression levels of the tumors were studied. Obatoclax synergized with SAHA and LBH589 and sensitized cells to HDACi/RTx. Over 50% of GSC cultures were responsive to Obatoclax with either single agent. Combined with HDACi/RTx treatment, Obatoclax increased caspase-3/7 and inhibited Bcl-2 family proteins Bcl-XL and Mcl-1 more effectively than other treatments. Genes predictive for treatment response were identified, including the F-box/WD repeat-containing protein-7, which was previously related to Bcl-2 inhibition and HDACi sensitivity. We emphasize the functional relation between Bcl-2 proteins and radiosensitization by HDACi and provide a target for increasing responsiveness in glioblastoma by using the Bcl-2 inhibitor Obatoclax.
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spelling pubmed-42794412015-01-07 The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells Berghauser Pont, Lotte M.E. Spoor, Jochem K.H. Venkatesan, Subramanian Swagemakers, Sigrid Kloezeman, Jenneke J. Dirven, Clemens M.F. van der Spek, Peter J. Lamfers, Martine L.M. Leenstra, Sieger Genes Cancer Research Paper Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers in cultures with Bcl-XL over-expression. We study the efficacy of SAHA/RTx and LBH589/RTx when manipulating Bcl-2 family proteins using the Bcl-2 inhibitor Obatoclax in patient-derived glioblastoma stem-like cell (GSC) cultures. GSC cultures in general have a deletion in phosphatase and tensin homolog (PTEN). Synergy was determined by the Chou Talalay method. The effects on apoptosis and autophagy were studied by measuring caspase-3/7, Bcl-XL, Mcl-1 and LC3BI/II proteins. The relation between treatment response and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, recurrence and gene expression levels of the tumors were studied. Obatoclax synergized with SAHA and LBH589 and sensitized cells to HDACi/RTx. Over 50% of GSC cultures were responsive to Obatoclax with either single agent. Combined with HDACi/RTx treatment, Obatoclax increased caspase-3/7 and inhibited Bcl-2 family proteins Bcl-XL and Mcl-1 more effectively than other treatments. Genes predictive for treatment response were identified, including the F-box/WD repeat-containing protein-7, which was previously related to Bcl-2 inhibition and HDACi sensitivity. We emphasize the functional relation between Bcl-2 proteins and radiosensitization by HDACi and provide a target for increasing responsiveness in glioblastoma by using the Bcl-2 inhibitor Obatoclax. Impact Journals LLC 2014-11 /pmc/articles/PMC4279441/ /pubmed/25568669 Text en Copyright: © 2014 Berghauser Pont et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Berghauser Pont, Lotte M.E.
Spoor, Jochem K.H.
Venkatesan, Subramanian
Swagemakers, Sigrid
Kloezeman, Jenneke J.
Dirven, Clemens M.F.
van der Spek, Peter J.
Lamfers, Martine L.M.
Leenstra, Sieger
The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells
title The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells
title_full The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells
title_fullStr The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells
title_full_unstemmed The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells
title_short The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells
title_sort bcl-2 inhibitor obatoclax overcomes resistance to histone deacetylase inhibitors saha and lbh589 as radiosensitizers in patient-derived glioblastoma stem-like cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279441/
https://www.ncbi.nlm.nih.gov/pubmed/25568669
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