Screening of anti-glioma effects induced by sigma-1 receptor ligands: potential new use for old anti-psychiatric medicines.

The prognosis of glioblastoma (GBM) remains poor. Diffuse invasion of distant brain tissue by migrating cells from the primary tumour mass has already occurred at time of diagnosis. Anti-cancer effects of a selective sigma-1 agonist, 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), in glioblastoma were shown previously, leading to the present work where the effects on glioblastoma cells of 17 agonists or antagonists of sigma-1 receptors were studied, including currently marketed drugs fluvoxamine, dextromethorphan, donepezil, memantine and haloperidol. We first showed that established GBM cell lines, primary cultures and surgical specimens express sigma-1 receptors. In vitro analyses then focused on anti-proliferation and anti-migratory effects on human glioblastoma cell lines using quantitative videomicroscopy analyses. These cell monitoring assays revealed specific impacts on the mitotic cell process. Using an aggressive glioma model orthotopically grafted into the brains of immunocompromised mice, we showed that combining donepezil and temozolomide gave additive benefit in terms of long survivors as compared to temozolomide or donepezil alone. Clinical study is planned if further rodent dose-ranging studies of donepezil with temozolomide continue to show evidence of benefit in this model.