Tumor-inhibition effect of levetiracetam in combination with temozolomide in glioblastoma cells

Abstract

Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis. The standard postoperative chemotherapy is temozolomide (TMZ), which does not greatly improve survival. The DNA repair gene O-6-methylguanine-DNA methyltransferase (MGMT) contributes to the response of TMZ-induced DNA damage. The commonly prescribed antiepileptic drug levetiracetam (LEV) has been shown to enhance TMZ’s antitumor effect via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of the LEV and TMZ combination remain poorly understood. Mechanisms of response to chemotherapy include apoptosis and mitotic catastrophe, and recent studies have suggested that premature senescence may also be invoked when cancer cells are exposed to therapeutic agents. In our study, we evaluated cell proliferation and premature senescence after single and combined treatments of TMZ and LEV in two GBM cell lines that differ in TMZ sensitivity caused by the absence (A172) or presence (T98) of the MGMT protein. Both LEV and TMZ reduced cell proliferation in a dose-dependent manner in A172 cells. A senescent-like phenotype, as determined by β-galactosidase activity, was induced by both TMZ and LEV. Overall, there was a greater effect following combined treatment compared to the monotherapy groups. Thus, LEV appears to have a tumor-suppressive effect and induces cellular senescence, and combined treatment of LEV and TMZ enhanced these effects. because LEV treatment results in few adverse effects, its use in GBM treatment may allow for reduction of the TMZ dose to enhance the clinical efficacy of TMZ chemotherapy and improve quality of life.