title: The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Lotte M E
authors.initials: LM
authors.lastname: Berghauser Pont
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jochem K H
authors.initials: JK
authors.lastname: Spoor
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Venkatesan
authors.affiliation: Department of Bio-informatics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Swagemakers
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jenneke J
authors.initials: JJ
authors.lastname: Kloezeman
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Clemens M F
authors.initials: CM
authors.lastname: Dirven
authors.affiliation: Department of Bio-informatics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Spek
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Martine L M
authors.initials: ML
authors.lastname: Lamfers
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands ; Department of Neurosurgery, Elisabeth Medical Hospital, Tilburg, The Netherlands.
authors.forename: Sieger
authors.initials: S
authors.lastname: Leenstra
keywords: Bcl-2; Bcl-XL; HDAC inhibitor; LBH589; Obatoclax; SAHA; radiation