Research Papers:

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 and Suzie Chen

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Oncotarget. 2019; 10:2824-2834. https://doi.org/10.18632/oncotarget.26854

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Atif J. Khan1,2, Stephanie LaCava2,3, Monal Mehta2, Devora Schiff2, Aditya Thandoni2, Sachin Jhawar2, Shabbar Danish4, Bruce G. Haffty2 and Suzie Chen3

1 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

2 Department of Radiation Oncology, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA

3 Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, USA

4 Department of Surgery, Division of Neurosurgery, Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA

Correspondence to:

Atif J. Khan,email: [email protected]

Keywords: glutamate; glioma; riluzole; radiation therapy

Received: December 29, 2018     Accepted: March 23, 2019     Published: April 19, 2019


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 patient-derived 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 γ-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 glutamate-release inhibitor riluzole sensitizes glioma cells to radiation and leads to greater cytotoxicity; these results have clinical implications for patients with glioblastoma.

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