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    A distinct reactive oxygen species profile confers chemoresistance in glioma-propagating cells and associates with patient survival outcome

    Access Status
    Fulltext not available
    Authors
    Koh, L.
    Koh, G.
    Ng, F.
    Toh, T.
    Sandanaraj, E.
    Chong, Y.
    Phong, M.
    Tucker-Kellogg, G.
    Kon, O.
    Ng, W.
    Ng, I.
    Clement, M.
    Pervaiz, Shazib
    Ang, B.
    Tang, C.
    Date
    2013
    Type
    Journal Article
    
    Metadata
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    Citation
    Koh, L. and Koh, G. and Ng, F. and Toh, T. and Sandanaraj, E. and Chong, Y. and Phong, M. et al. 2013. A distinct reactive oxygen species profile confers chemoresistance in glioma-propagating cells and associates with patient survival outcome. Antioxidants and Redox Signaling. 19 (18): pp. 2261-2279.
    Source Title
    Antioxidants and Redox Signaling
    DOI
    10.1089/ars.2012.4999
    ISSN
    1523-0864
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/51146
    Collection
    • Curtin Research Publications
    Abstract

    Aims: We explore the role of an elevated O2-:H 2O2 ratio as a prosurvival signal in glioma-propagating cells (GPCs). We hypothesize that depleting this ratio sensitizes GPCs to apoptotic triggers. Results: We observed that an elevated O2-:H2O2 ratio conferred enhanced resistance in GPCs, and depletion of this ratio by pharmacological and genetic methods sensitized cells to apoptotic triggers. We established the reactive oxygen species (ROS) Index as a quantitative measure of a normalized O2-:H2O2 ratio and determined its utility in predicting chemosensitivity. Importantly, mice implanted with GPCs of a reduced ROS Index demonstrated extended survival. Analysis of tumor sections revealed effective targeting of complementarity determinant 133 (CD133)- and nestin-expressing neural precursors. Further, we established the Connectivity Map to interrogate a gene signature derived from a varied ROS Index for the patterns of association with individual patient gene expression in four clinical databases. We showed that patients with a reduced ROS Index demonstrate better survival. These data provide clinical evidence for the viability of our O 2-:H2O2-mediated chemosensitivity profiles. Innovation and Conclusion: Gliomas are notoriously recurrent and highly infiltrative, and have been shown to arise from stem-like cells. We implicate an elevated O2-:H2O2 ratio as a prosurvival signal in GPC self-renewal and proliferation. The ROS Index provides quantification of O2-:H2O 2-mediated chemosensitivity, an advancement in a previously qualitative field. Intriguingly, glioma patients with a reduced ROS Index correlate with longer survival and the Proneural molecular classification, a feature frequently associated with tumors of better prognosis. These data emphasize the feasibility of manipulating the O2-:H 2O2 ratio as a therapeutic strategy. Antioxid. Redox Signal. 19, 2261-2279. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

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