Riluzole: a potential therapeutic intervention in human brain tumor stem-like cells

// Swetlana Sperling 1 , Thiha Aung 2 , Sabine Martin 3, 4 , Veit Rohde 1 and Milena Ninkovic 1 1 The Translational Neurooncology Research Group, Department of Neurosurgery, University Medical Center Gottingen, University Gottingen, Gottingen, Germany 2 Center of Plastic, Hand and Reconstructive Surgery, University Medical Center Regensburg, Regensburg, Germany 3 Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Gottingen, Germany 4 Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Gottingen, Germany Correspondence to: Milena Ninkovic, email: milena.ninkovic@med.uni-goettingen.de Keywords: riluzole, human brain tumor stem-like cells, GLUT3, DNMT1, cell death Received: June 09, 2016      Accepted: May 15, 2017      Published: May 20, 2017 ABSTRACT A small subpopulation of tumor stem-like cells has the capacity to initiate tumors and mediate radio- and chemoresistance in diverse cancers hence also in glioblastoma (GBM). It has been reported that this capacity of tumor initiation in the brain is mainly dependent on the body’s nutrient supply. This population of so-called brain tumor initiating or brain tumor stem-like cells (BTSCs) is able to extract nutrients like glucose with a higher affinity. Riluzole, a drug approved for treating amyotrophic lateral sclerosis (ALS), was reported to possess anticancer properties, affecting the glutamate metabolism. We report that riluzole treatment inhibits the growth of brain tumor stem-like cells enriched cultures isolated from two human glioblastomas. The effects of riluzole on these cells were associated with an inhibition of a poor prognostic indicator: glucose transporter 3 (GLUT3). A decrease in GLUT3 is associated with a decrease in the p-Akt/HIF1α pathway. Further, downregulation of the DNA (Cytosine-5-)-methyltransferase 1 (DNMT1) gene that causes hypermethylation of various tumor-suppressor genes and leads to a poor prognosis in GBM, was detected. Two hallmarks of cancer cells—proliferation and cell death—were positively influenced by riluzole treatment. Finally, we observed that riluzole reduced the tumor growth in in vivo CAM assay, suggesting it could be a possible synergistic drug for the treatment of glioblastoma.