Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells

// Dinesh Thotala 1, 4 , Rowan M. Karvas 1 , John A. Engelbach 3 , Joel R. Garbow 2, 3, 4 , Andrew N. Hallahan 1 , Todd A. DeWees 1 , Andrei Laszlo 1 , Dennis E. Hallahan 1, 3, 4, 5 1 Department of Radiation Oncology, Washington University in St. Louis, Missouri, USA 2 School of Medicine, Washington University in St. Louis, Missouri, USA 3 Mallinckrodt Institute of Radiology, Washington University in St. Louis, Missouri, USA 4 Siteman Cancer Center, Washington University in St. Louis, Missouri, USA 5 Hope Center, Washington University in St. Louis, Missouri, USA Correspondence to: Dennis E. Hallahan, e-mail: dhallahan@radonc.wustl.edu Keywords: valproic acid (VPA), neuroprotection, histone deacetylase (HDAC), radioprotection, cancer therapy Received: May 29, 2014 Accepted: September 04, 2015 Published: September 16, 2015 ABSTRACT Neurocognitive deficits are serious sequelae that follow cranial irradiation used to treat patients with medulloblastoma and other brain neoplasms. Cranial irradiation causes apoptosis in the subgranular zone of the hippocampus leading to cognitive deficits. Valproic acid (VPA) treatment protected hippocampal neurons from radiation-induced damage in both cell culture and animal models. Radioprotection was observed in VPA-treated neuronal cells compared to cells treated with radiation alone. This protection is specific to normal neuronal cells and did not extend to cancer cells. In fact, VPA acted as a radiosensitizer in brain cancer cells. VPA treatment induced cell cycle arrest in cancer cells but not in normal neuronal cells. The level of anti-apoptotic protein Bcl-2 was increased and the pro-apoptotic protein Bax was reduced in VPA treated normal cells. VPA inhibited the activities of histone deacetylase (HDAC) and glycogen synthase kinase-3β (GSK3β), the latter of which is only inhibited in normal cells. The combination of VPA and radiation was most effective in inhibiting tumor growth in heterotopic brain tumor models. An intracranial orthotopic glioma tumor model was used to evaluate tumor growth by using dynamic contrast-enhanced magnetic resonance (DCE MRI) and mouse survival following treatment with VPA and radiation. VPA, in combination with radiation, significantly delayed tumor growth and improved mouse survival. Overall, VPA protects normal hippocampal neurons and not cancer cells from radiation-induced cytotoxicity both in vitro and in vivo . VPA treatment has the potential for attenuating neurocognitive deficits associated with cranial irradiation while enhancing the efficiency of glioma radiotherapy.