Riluzole Reverses a Number of Undesirable Effects of Dexamethasone in Glioblastoma Cells

Abstract

Background/Aim: Glioblastoma multiforme (GBM)induced oedema is a major cause of morbidity and mortality among patients with GBM. Dexamethasone (Dex) is the most common corticosteroid used pre-operatively to control cerebral oedema in patients with GBM. Dex is associated with many side effects, and shorter overall survival and progression-free survival of patients with GBM. These negative effects of Dex highlight the need for combinational therapy. Riluzole (Ril), a drug used to treat amyotrophic lateral sclerosis (ALS), is thought to have potential as a treatment for various cancers, with clinical trials underway. Here, we investigated whether Ril could reverse some of the undesirable effects of Dex. Materials and Methods: The effect of Dex, Ril, and Ril-Dex treatment on cell migration was monitored using the xCELLigence system. Cell viability assays were performed using 3-(4, 5dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT). The expression of genes involved in migration, glucose metabolism, and stemness was examined using real-time polymerase chain reaction (PCR). Results: Pre-treating GBM cells with Ril reduced Dex-induced cell migration and altered Dex-induced effects on cell invasion, stem cell, and glucose metabolism markers. Furthermore, Ril remained effective in killing GBM cells in combination with Dex. Conclusion: Ril, which acts as an anti-tumorigenic drug, mediates some of the negative effects of Dex; therefore, it could be a potential drug to manage the side effects of Dex therapy in GBM.Among brain tumours, glioblastoma multiforme (GBM) is the most common and most aggressive. Standard therapy consists of surgical resection, radiotherapy and chemotherapy. Cerebral oedema is a major cause of morbidity and mortality in GBM due to the high risk of brain herniation [in up to 60% of GBM patients, reviewed in (1)]. Corticosteroids are commonly used pre-operatively to control cerebral oedema and post-operatively to combat side effects. Dexamethasone (Dex) is the preferred corticosteroid due to its ability to decrease the permeability of the blood-brain barrier. Additional benefits of Dex use in patients with cancer are its ability to control tumor-associated pain, nausea and vomiting and to improve appetite (2). Unfortunately, besides the positive effects of Dex, many side effects, such as abnormal glucose metabolism, gastrointestinal complications, insomnia, and anxiety, have been reported (3). The use of Dex is also associated with shorter overall survival and progression-free survival of patients with GBM (4).Important correlations between Dex treatment and alterations in gene expression profiles have been identified (5). In a study that included patients with mesenchymal and proneural GBM, Dex-controlled gene network and pathways closely related to proliferation, invasion and angiogenesis were significantly upregulated in the mesenchymal group. Dex was also shown to increase the invasion and proliferation of cells derived from patients with GBM, highlighting that Dex can increase tumor aggressive...