Repurposing the anti-epileptic drug sodium valproate as an adjuvant treatment for diffuse intrinsic pontine glioma

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.

Oxaliplatin and [Pt(R,R-DACH)(panobinostat-2H)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG)

“…S37 †). Cytotoxicity values for carboplatin 4,6 and panobinostat 6 have previously been reported in DIPG cell lines, but we could find no reports evaluating either oxaliplatin or SubH for DIPG. We used three well-characterised, patient-derived, low passage DIPG cell lines with different mutational statuses in the key driver mutations (H3K27M and ALK2).…”

“…cell lines DUB D003: IC 50 0.047 mg mL −1 ; SF8628 IC 50 0.026 mg mL −1 and SF7761 IC 50 0.0048 mg mL −1 ). 4…”

“…2 A key challenge for the therapeutic treatment of DIPG is the delivery of agents across the typically intact blood brain barrier (BBB). 3 Combined therapies such as carboplatin and the histone deacetylase (HDAC) inhibitor sodium valproate are reportedly synergistic towards DIPG in cellulo 4 and direct delivery of these agents to the brainstem by convection-enhanced delivery (CED) is used clinically. 5 DIPG cell lines 6 and xenograft models 6,7 also demonstrate sensitivity to the potent broad-spectrum HDAC inhibitor panobinostat ( Fig.…”

Combined use of CDK4/6 and mTOR inhibitors induce synergistic growth arrest of diffuse intrinsic pontine glioma cells via mutual downregulation of mTORC1 activity

“…Drug synergy analysis, based on cell viability assays, compared single-agent treatments to equivalent combination treatments, as previously described. 13 Statistical analyses were conducted using GraphPad Prism 6 and MiniTab 17. All values are expressed as mean of triplicate determinations ± SEM.…”

Prolonged survival in a patient with a cervical spine H3K27M-mutant diffuse midline glioma

“…The patient was started on lomustine, but this was stopped after three cycles due to progression of disease on MRI. Twenty-five months after diagnosis, the patient had further disease progression and was initiated on valproic acid, a histone deacetylase (HDAC) inhibitor, with the aim of targeting the H3 mutation 11…”