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 xc-, 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 xc- for their
glutathione synthesis. Inhibition of system xc- 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 xc-. 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 xc- may be a viable therapeutic strategy with a Food and Drug Administration-approved drug already in hand.