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


FOR IMMEDIATE RELEASE
2019-10-29

The cover for issue 29 of Oncotarget features Figure 6, "RIL + RT reduces anchorage-independent colony growth of glioma cells," by Khan, et al.

The research team evaluated the effect of riluzole on glioma cells.

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.

GRM3 was expressed in most tested glioma samples, and strongly expressed in some.

The team 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.

Dr. Atif J. Khan from the Department of Radiation Oncology, at the Memorial Sloan Kettering Cancer Center, in New York, New York 10065, USA and the Department of Radiation Oncology, at Rutgers-Robert Wood Johnson Medical School, in Piscataway, New Jersey 08854, USA said, "High-grade gliomas are particularly vexing tumors that indiscriminately devastate both adults and children alike."

The excitatory amino acid transporters 1 and 2 are Na2+ dependent glutamate transporters expressed on normal astrocytes that maintain extracellular glutamate levels at uM concentrations by uptaking glutamate.

Glioma cells lack expression of EATT2 and appear to have EATT1 mislocalized to the nucleus, resulting in no functional glutamate uptake.

Savaskan et al., have conclusively demonstrated that xCT levels are elevated in gliomas, xCT ablation by si RNA results in massive reduction in glutamate secretion, and that conditioned media from glioma cells results in neuronal degeneration only if xCT is functional.

Ciceroni et al., have demonstrated that glioma-initiating CD133-positive stem cells express the metabotropic glutamate receptor 3 and that pharmacologic blockade of mGlu R3 results in committed differentiation into benign astrocyte-like cells.

The author?s discovery that riluzole induces DNA damage, likely mediated by a reduction in glutathione levels within the transformed cells, opens up possibilities of combining riluzole with agents such as ionizing radiation that increases sensitivity in cells with damaged DNA.

The Khan research team concluded, "Taken together, our work as well as that of others leads us to our current working hypothesis in which overexpression of system Xc in gliomas increases intracellular glutathione and increases extracellular glutamate which then acts as a paracrine/autocrine trophic factor for glioma progression through stimulation of GRM3."

Full text - https://doi.org/10.18632/oncotarget.26854

Correspondence to - Atif J. Khan - khana7@mskcc.org

Keywords - glutamate, glioma, riluzole, radiation therapy



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