Abstract
Targeting epigenetic changes in diffuse intrinsic pontine glioma (DIPG) may provide a novel treatment option for patients. This report demonstrates that sodium valproate, a histone deacetylase inhibitor (HDACi), can increase the cytotoxicity of carboplatin in an additive and synergistic manner in DIPG cells in vitro. Sodium valproate causes a dose-dependent decrease in DIPG cell viability in three independent ex vivo cell lines. Furthermore, sodium valproate caused an increase in acetylation of histone H3. Changes in cell viability were consistent with an induction of apoptosis in DIPG cells in vitro, determined by flow cytometric analysis of Annexin V staining and assessment of apoptotic markers by western blotting. Subsequently, immunofluorescent staining of neuronal and glial markers was used to determine toxicity in normal rat hippocampal cells. Pre-treatment of cells with sodium valproate enhanced the cytotoxic effects of carboplatin, in three DIPG cell lines tested. These results demonstrate that sodium valproate causes increased histone H3 acetylation indicative of HDAC inhibition, which is inversely correlated with a reduction in cell viability. Cell viability is reduced through an induction of apoptosis in DIPG cells. Sodium valproate potentiates carboplatin cytotoxicity and prompts further work to define the mechanism responsible for the synergy between these two drugs and determine in vivo efficacy. These findings support the use of sodium valproate as an adjuvant treatment for DIPG.
Highlights
Whilst great advances have been made in the characterisation of the molecular changes in diffuse intrinsic pontine glioma (DIPG), the clinical challenges that oppose treatment strategies remain set in place
The DUB-D003 cell line was established from a surgical biopsy and carries a HIST1H3B gene mutation (K27M H3.1), this cell line was obtained from Chris Jones (Institute of Cancer Research, London, UK) and maintained in neurobasal A medium (NBA) supplemented with epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF)-AA (Shenandoah Biotech), PDGF-BB (Shenandoah Biotech), B-27 and heparin (StemCell Technologies)
Sodium valproate had a dose-dependent effect on cell viability (Fig 1A) in all three mutant Histone H3 ex vivo cell lines
Summary
Whilst great advances have been made in the characterisation of the molecular changes in DIPG, the clinical challenges that oppose treatment strategies remain set in place. Previous clinical trials have been reliant on the assumption of similar genetics between adult high grade glioma and DIPG, recent discoveries of H3F3A and AVCR1 mutations have led to the emergence of several preclinical studies with DIPG targeted therapies [1,2,3,4,5,6]. The current DIPG treatment regime consists of radiotherapy that provides only a palliative response for patients and it is well known that cranial radiation alone in children can cause neurological. Repurposing sodium valproate as an adjuvant treatment for DIPG
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