ET-50 * LEVETIRACETAM DOWNREGULATES O6-METHYLGUANINE DNA METHYLTRANSFERASE EXPRESSION AND SENSITIZES TEMOZOLOMIDE-RESISTANT GLIOMA CELLS

Abstract

Temozolomide (TMZ) has become a key agent in treating malignant glioma; nevertheless, its survival benefit remains dismal prognosis. Histone deacetylases are often overexpressed in cancer cells, and this leads to altered expression and activity of numerous proteins involved in carcinogenesis. Recent evidence suggests that expression of class I histone deacetylases is higher in malignant gliomas and is important in resistance to TMZ. Levetiracetam (LEV) is an antiepileptic drug that inhibits histone deacetylases, but the therapeutic effects of a combination regimen comprising LEV and TMZ are poorly understood. In this study, we found that the antitumor effects of LEV are potentiated by combining it with TMZ, especially in TMZ-resistant cell lines. This combination significantly enhanced antitumor effects against the TMZ-resistant malignant glioma cell lines T98 and U138. This enhanced antitumor effect correlated with LEV-mediated reduction in O6-methylguanine DNA methyltransferase expression, which is important in cellular resistance to alkylating agents. In vitro, this combination enhanced apoptotic and autophagic cell death and suppressed migratory activities in the TMZ-resistant cell lines. Furthermore, an in vivo efficacy studies using an intracranial tumor model showed that combination therapy significantly increased median survival as compared with monotherapy groups. Our results warrant further studies to test the efficacy of combined TMZ and LEV chemotherapy in malignant glioma.