Synergistic Effect of Perampanel and Temozolomide in Human Glioma Cell Lines.

Andrea Salmaggi,Sara Donzelli,Annachiara D'Urso,Emilio Ciusani,Cristina Corno,Marta Maschio,Paola Perego

doi:10.3390/jpm11050390

Abstract

Glioblastoma is characterized by a high proliferative rate and drug resistance. The standard of care includes maximal safe surgery, followed by radiotherapy and temozolomide chemotherapy. The expression of glutamate receptors has been previously reported in human glioma cell lines. The aim of this study was to examine the cellular effects of perampanel, a broad-spectrum antiepileptic drug acting as an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) glutamate receptor antagonist, alone or in combination with temozolomide. Four human glioma cell lines were exposed to different concentrations of perampanel and temozolomide, alone or in combination. The type of drug interaction was assessed using the Chou-Talalay method. Apoptosis, cell cycle perturbation, and glutamate receptors (GluRs) subunit expression were assessed by flow cytometry. Perampanel significantly inhibited the growth, inducing high levels of apoptosis. A strong synergistic effect of the combination of perampanel with temozolomide was detected in U87 and A172, but not in U138. Treatment with perampanel resulted in an increased GluR2/3 subunit expression in U87 and U138. Perampanel displays a pro-apoptotic effect on human glioblastoma cell lines when used alone, possibly due to increased GluR2/3 expression. The observed synergistic effect of the combination of temozolomide with perampanel suggests further investigation on the impact of this combination on oncologic outcomes in glioblastoma.

Highlights

Gliomas are the most frequent malignant primary intracranial tumors, with an estimated incidence of 6–8 cases/100.000/year
After the 2009 clinical trial by Grossman [9], with median overall survival reaching 20 months in Talampanel-treated GBM patients vs. 14.6 months in the active treatment arm of the Stupp 2005 trial [16], and a proportion of 24-month survival of 40% vs. 27%, data from Iwamoto, showing no significant activity as a single agent in unselected recurrent malignant gliomas in terms of overall survival and progression free survival [17], appeared less promising, and no further clinical trials were performed with this molecule in the management of high grade glioma
The development and availability of perampanel as an add-on treatment in epilepsy with focal onset has led to widespread clinical use of this drug, mainly for resistant and refractory epilepsies [18]

Summary

Introduction

Gliomas are the most frequent malignant primary intracranial tumors, with an estimated incidence of 6–8 cases/100.000/year. With the exception of grade I glioma, these tumors invariably progress intracranially, despite all available treatment modalities, leading to disability and death. Mutations at multiple levels lead to deranged cell function, uncontrolled proliferation, and migration of glioma cells [3]. A number of pathways and mediators are involved in these features; among these, the glutamatergic pathway has been shown to be upregulated in high-grade glioma with enhanced release of glutamate by high grade glioma cells, which sustain glioma cell proliferation and migration [4]. Glutamate is produced in excess by tumor cells, induces neuronal cell death, and enhances proliferation and resistance to apoptosis, as well as migration of tumor cells [5]. Glutamate is implicated in the growth of glioma, and in induction of seizures, a frequent clinical manifestation found in glioma [7]

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