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Neurobiology of Disease

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Wook Joon Chung, Susan A. Lyons, Gina M. Nelson, Hashir Hamza, Candece L. Gladson, G. Yancey Gillespie and Harald Sontheimer
Journal of Neuroscience 3 August 2005, 25 (31) 7101-7110; DOI: https://doi.org/10.1523/JNEUROSCI.5258-04.2005
Wook Joon Chung
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Susan A. Lyons
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Gina M. Nelson
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Hashir Hamza
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Candece L. Gladson
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G. Yancey Gillespie
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Harald Sontheimer
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Abstract

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

  • excitotoxicity
  • glutathione
  • glutamate transport
  • glial progenitor cells
  • sulfasalazine
  • (S)-4-carboxyphenylglycine
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The Journal of Neuroscience: 25 (31)
Journal of Neuroscience
Vol. 25, Issue 31
3 Aug 2005
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Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors
Wook Joon Chung, Susan A. Lyons, Gina M. Nelson, Hashir Hamza, Candece L. Gladson, G. Yancey Gillespie, Harald Sontheimer
Journal of Neuroscience 3 August 2005, 25 (31) 7101-7110; DOI: 10.1523/JNEUROSCI.5258-04.2005

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Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors
Wook Joon Chung, Susan A. Lyons, Gina M. Nelson, Hashir Hamza, Candece L. Gladson, G. Yancey Gillespie, Harald Sontheimer
Journal of Neuroscience 3 August 2005, 25 (31) 7101-7110; DOI: 10.1523/JNEUROSCI.5258-04.2005
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