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.