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    Computational modelling of LY303511 and TRAIL-induced apoptosis suggests dynamic regulation of cFLIP

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    Fulltext not available
    Authors
    Shi, Y.
    Mellier, G.
    Huang, S.
    White, J.
    Pervaiz, Shazib
    Tucker-Kellogg, L.
    Date
    2013
    Type
    Journal Article
    
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    Citation
    Shi, Y. and Mellier, G. and Huang, S. and White, J. and Pervaiz, S. and Tucker-Kellogg, L. 2013. Computational modelling of LY303511 and TRAIL-induced apoptosis suggests dynamic regulation of cFLIP. Bioinformatics. 29 (3): pp. 347-354.
    Source Title
    Bioinformatics
    DOI
    10.1093/bioinformatics/bts702
    ISSN
    1367-4803
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/51294
    Collection
    • Curtin Research Publications
    Abstract

    Motivation: TRAIL has been widely studied for the ability to kill cancer cells selectively, but its clinical usefulness has been hindered by the development of resistance. Multiple compounds have been identified that sensitize cancer cells to TRAIL-induced apoptosis. The drug LY303511 (LY30), combined with TRAIL, caused synergistic (greater than additive) killing of multiple cancer cell lines. We used mathematical modelling and ordinary differential equations to represent how LY30 and TRAIL individually affect HeLa cells, and to predict how the combined treatment achieves synergy.Results: Model-based predictions were compared with in vitro experiments. The combination treatment model was successful at mimicking the synergistic levels of cell death caused by LY30 and TRAIL combined. However, there were significant failures of the model to mimic upstream activation at early time points, particularly the slope of caspase-8 activation. This flaw in the model led us to perform additional measurements of early caspase-8 activation. Surprisingly, caspase-8 exhibited a transient decrease in activity after LY30 treatment, prior to strong activation. cFLIP, an inhibitor of caspase-8 activation, was up-regulated briefly after 30 min of LY30 treatment, followed by a significant down-regulation over prolonged exposure. A further model suggested that LY30-induced fluctuation of cFLIP might result from tilting the ratio of two key species of reactive oxygen species (ROS), superoxide and hydrogen peroxide. Computational modelling extracted novel biological implications from measured dynamics, identified time intervals with unexplained effects, and clarified the non-monotonic effects of the drug LY30 on cFLIP during cancer cell apoptosis.Supplementary information: Supplementary data are available at Bioinformatics online. © 2012 The Author.

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