Riluzole exerts distinct antitumor effects from a metabotropic glutamate receptor 1-specific inhibitor on breast cancer cells

// Sonia C. Dolfi 1 , Daniel J. Medina 1 , Aparna Kareddula 1 , Bhavna Paratala 1 , Ashley Rose 1 , Jatinder Dhami 1 , Suzie Chen 2 , Shridar Ganesan 1 , Gillian Mackay 3 , Alexei Vazquez 3 and Kim M. Hirshfield 1 1 Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA 2 Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA 3 CRUK Beatson Institute, Garscube Estate, Bearsden, Glasgow G61 1BD, UK Correspondence to: Kim M. Hirshfield, email: hirshfie@cinj.rutgers.edu Keywords: riluzole, breast cancer, glutamate signaling, cell cycle, BAY 36-7620 Received: September 09, 2016      Accepted: April 20, 2017      Published: May 18, 2017 ABSTRACT Recent evidence suggests that glutamate signaling plays an important role in cancer. Riluzole is a glutamate release inhibitor and FDA-approved drug for the treatment of amyotrophic lateral sclerosis. It has been investigated as an inhibitor of cancer cell growth and tumorigenesis with the intention of repurposing it for the treatment of cancer. Riluzole is thought to act by indirectly inhibiting glutamate signaling. However, the specific effects of riluzole in breast cancer cells are not well understood. In this study, the anti-cancer effects of riluzole were explored in a panel of breast cancer cell lines in comparison to the metabotropic glutamate receptor 1-specific inhibitor BAY 36-7620. While both drugs inhibited breast cancer cell proliferation, there were distinct functional effects suggesting that riluzole action may be metabotropic glutamate receptor 1-independent. Riluzole induced mitotic arrest independent of oxidative stress while BAY 36-7620 had no measurable effect on mitosis. BAY 36-7620 had a more pronounced and significant effect on DNA damage than riluzole. Riluzole altered cellular metabolism as demonstrated by changes in oxidative phosphorylation and cellular metabolite levels. These results provide a better understanding of the functional action of riluzole in the treatment of breast cancer.