Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 31, Pages 7101-7110Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5258-04.2005
Keywords
excitotoxicity; glutathione; glutamate transport; glial progenitor cells; sulfasalazine; (S)-4-carboxyphenylglycine
Categories
Funding
- NCI NIH HHS [P50 CA097247, P50CA97247, P50 CA097247-010003] Funding Source: Medline
- NINDS NIH HHS [R01 NS052634-03, R01 NS036692-05A1, R01 NS052634-02, R01 NS052634-04, R01 NS036692-07, R01 NS052634, R01-NS36692, R01 NS036692-06, R01 NS036692] Funding Source: Medline
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Glial cells play an important role in sequestering neuronally released glutamate via Na+-dependent transporters. Surprisingly, these transporters are not operational in glial-derived tumors ( gliomas). Instead, gliomas release glutamate, causing excitotoxic death of neurons in the vicinity of the tumor. We now show that glutamate release from glioma cells is an obligatory by-product of cellular cystine uptake via system x(c)(-), an electroneutral cystine-glutamate exchanger. Cystine is an essential precursor for the biosynthesis of glutathione, a major redox regulatory molecule that protects cells from endogenously produced reactive oxygen species ( ROS). Glioma cells, but not neurons or astrocytes, rely primarily on cystine uptake via system x(c)(-) for their glutathione synthesis. Inhibition of system x(c)(-) causes a rapid depletion of glutathione, and the resulting loss of ROS defense causes caspase-mediated apoptosis. Glioma cells can be rescued if glutathione status is experimentally restored or if glutathione is substituted by alternate cellular antioxidants, confirming that ROS are indeed mediators of cell death. We describe two potent drugs that permit pharmacological inhibition of system x(c)(-). One of these drugs, sulfasalazine, is clinically used to treat inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine was able to reduce glutathione levels in tumor tissue and slow tumor growth in vivo in a commonly used intracranial xenograft animal model for human gliomas when administered by intraperitoneal injection. These data suggest that inhibition of cystine uptake into glioma cells through the pharmacological inhibition of system x(c)(-) maybe a viable therapeutic strategy with a Food and Drug Administration-approved drug already in hand.
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