Repurposing an Antiepileptic Drug for the Treatment of Glioblastoma

Abstract

Glioblastoma multiforme (GBM) is a grade IV malignant glioma. It is a highly proliferative brain tumor with the 5-year survival rate close to 5% indicating a high mortality rate. Current treatment strategies include surgery, radiation, and chemotherapy. Development of resistance against the current treatment options and the blood brain barrier (BBB) pose major challenges in GBM management. Therefore, we studied an FDA-approved drug stiripentol which is used for Dravet's syndrome (a rare form of epilepsy) for its efficacy in GBM. Stiripentol decreased the cytotoxicity in U87 and U138 astrocytoma cells. Cell proliferation and clonogenic survival of U87 cells was also adversely affected by stiripentol. Cellular anticancer activity was studied by cell cycle assay, apoptosis assay by flow cytometry, and by measuring the expression of apoptotic markers by Western blotting. In addition, effect of stiripentol on key cell signaling proteins was determined using Western blotting. Stiripentol treatment induced apoptosis and resulted in cell cycle arrest in GBM cells. 3D spheroid assay was performed to replicate the tumor environment and analyze the multidirectional metastatic growth of the cancer cells in presence of stiripentol and the standard GBM therapeutic Temozolomide (TMZ). Fluorescence imaging of spheroids demonstrated anticancer effects of stiripentol and TMZ. Further in vivo studies will be performed on xenograft models of astrocytoma cells. Our results indicate that stiripentol can be an effective GBM therapeutic and merits further investigation.