title: Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells.
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.
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, Missouri, USA.|Siteman Cancer Center, Washington University in St. Louis, Missouri, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Thotala
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, Missouri, USA.
authors.forename: Rowan M
authors.initials: RM
authors.lastname: Karvas
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University in St. Louis, Missouri, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Engelbach
authors.affiliation: School of Medicine, Washington University in St. Louis, Missouri, USA.|Mallinckrodt Institute of Radiology, Washington University in St. Louis, Missouri, USA.|Siteman Cancer Center, Washington University in St. Louis, Missouri, USA.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Garbow
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, Missouri, USA.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Hallahan
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, Missouri, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: DeWees
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, Missouri, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Laszlo
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, Missouri, USA.|Mallinckrodt Institute of Radiology, Washington University in St. Louis, Missouri, USA.|Siteman Cancer Center, Washington University in St. Louis, Missouri, USA.|Hope Center, Washington University in St. Louis, Missouri, USA.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D016371:Cranial Irradiation / Q000009:adverse effects; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005909:Glioblastoma / Q000473:pathology*; D006624:Hippocampus / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009474:Neurons / Q000187:drug effects* / Q000528:radiation effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D011832:Radiation Injuries / Q000517:prevention & control*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D011838:Radiation-Sensitizing Agents; D014635:Valproic Acid
keywords: cancer therapy; histone deacetylase (HDAC); neuroprotection; radioprotection; valproic acid (VPA)