RT Journal Article
SR Electronic
T1 Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7101
OP 7110
DO 10.1523/JNEUROSCI.5258-04.2005
VO 25
IS 31
A1 Wook Joon Chung
A1 Susan A. Lyons
A1 Gina M. Nelson
A1 Hashir Hamza
A1 Candece L. Gladson
A1 G. Yancey Gillespie
A1 Harald Sontheimer
YR 2005
UL http://www.jneurosci.org/content/25/31/7101.abstract
AB 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 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document}, 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 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document} for their glutathione synthesis. Inhibition of system \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document} 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 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document}. 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 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{x}_{\mathrm{c}}^{-}\) \end{document} may be a viable therapeutic strategy with a Food and Drug Administration-approved drug already in hand.