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.

Valproic Acid Promotes Human Glioma U87 Cells Apoptosis and Inhibits Glycogen Synthase Kinase-3β Through ERK/Akt Signaling

“…Interestingly, increasing evidence suggests that VPA had an anticancer effect in several GBM cell lines [10]. VPA treatment induced cell cycle arrest and enhanced the efficiency of glioma radiotherapy in clinical trials [11]. Also, VPA may show antineoplastic activity based on its gene-regulation functions [12][13][14][15][16].…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…Recent in vitro studies in cell lines have shown VPA to be a radiosensitizer in melanoma, breast cancer, osteosarcoma and colorectal cancer . Several in vivo and in vitro studies as well as clinical studies have also indicated that VPA has radiosensitizing effects for gliomas and is radioprotective to normal brain tissue . A Phase II trial of concurrent radiation therapy, temozolomide and VPA in patients with glioblastoma has reported promising treatment results, in terms of improved survival and PFS .…”

“…128 Several in vivo and in vitro studies as well as clinical studies have also indicated that VPA has radiosensitizing effects for gliomas and is radioprotective to normal brain tissue. [129][130][131] A Phase II trial of concurrent radiation therapy, temozolomide and VPA in patients with glioblastoma has reported promising treatment results, in terms of improved survival and PFS. 132 A retrospective analysis of 112 patients with high-grade glioma also concluded that the use of VPA during radiotherapy for glioma is associated with delayed hair loss and improvement in survival.…”

Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells

“…It has demonstrated neuroprotective effects against various insults through multiple cellular pathways. In addition, VPA has been shown to have anti-cancer effects against a wide variety of neoplasms [41][42][43][44][45][46][47][48]. The anti-tumor activity of VPA was reported to be attributed to its ability to inhibit histone deacetylase [13,49].…”