The glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo

Atif J. Khan, Stephanie LaCava, Monal Mehta, Devora Schiff, Aditya Thandoni, Sachin Jhawar, Shabbar Danish, Bruce G. Haffty, Suzie Chen

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Purpose: High-grade gliomas are lethal malignancies that cause morbidity and mortality due to local progression rather than metastatic spread. Our group has previously demonstrated that human GRM1 (hGRM1) is ectopically expressed in melanocytes leading to a transformed phenotype. Riluzole, a glutamate release inhibitor, leads to apoptotic cell death via DNA damage. Recent work has demonstrated the pathological significance of the related mGluR3/GRM3 (protein or gene: hGRM3) in gliomas. We evaluated the effect of riluzole on glioma cells. Experimental Design: Western blot analysis and immunofluorescence was performed to assess for GRM3 expression in commercially available and patientderived glioma cells and for functional analysis of GRM3 using receptor agonist/ antagonists and downstream effectors, ERK and AKT phosphorylation, as the read-out. Glutamate secretion by glioma cells was measured using ELISA. Flank and intracranial mouse xenograft models were used to assess growth delay with the glutamate release inhibitor, riluzole (RIL). Immunofluorescence was used to evaluate 53BP1 or ?-H2AX foci after RIL. Results: GRM3 was expressed in most tested glioma samples, and strongly expressed in some. Glioma cells were found to secrete glutamate in the extracellular space and to respond to receptor stimulation by activating downstream ERK. This signaling was abrogated by pretreatment with RIL. Treatment with RIL caused an increase in DNA damage markers, and an increase in cellular cytotoxicity in vitro and in vivo. Conclusions: We have demonstrated that pretreatment with the glutamaterelease inhibitor riluzole sensitizes glioma cells to radiation and leads to greater cytotoxicity; these results have clinical implications for patients with glioblastoma.

Original languageEnglish (US)
Pages (from-to)2824-2834
Number of pages11
JournalOncotarget
Volume10
Issue number29
DOIs
StatePublished - Apr 19 2019

All Science Journal Classification (ASJC) codes

  • Oncology

Keywords

  • Glioma
  • Glutamate
  • Radiation therapy
  • Riluzole

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