| Autor: |
Berghauser Pont LM; Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands., Spoor JK; Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands., Venkatesan S; Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands., Swagemakers S; Department of Bio-informatics, Erasmus MC, Rotterdam, The Netherlands., Kloezeman JJ; Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands., Dirven CM; Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands., van der Spek PJ; Department of Bio-informatics, Erasmus MC, Rotterdam, The Netherlands., Lamfers ML; Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands., Leenstra S; Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands ; Department of Neurosurgery, Elisabeth Medical Hospital, Tilburg, The Netherlands. |
| Abstrakt: |
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. |
