Human recombinant arginase I (Co)-PEG5000 [HuArgI (Co)-PEG5000]-induced arginine depletion is selectively cytotoxic to human glioblastoma cells

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dc.contributor.author Khoury, Oula
dc.contributor.author Ghazale, Noura
dc.contributor.author Stone, Everett
dc.contributor.author El-Sibai, Mirvat
dc.contributor.author Frankel, Arthur
dc.contributor.author Abi-Habib, Ralph J.
dc.date.accessioned 2015-12-01T07:41:40Z
dc.date.available 2015-12-01T07:41:40Z
dc.date.copyright 2015
dc.date.issued 2015-12-01
dc.identifier.issn 0167-594X en_US
dc.identifier.uri http://hdl.handle.net/10725/2739
dc.description.abstract In this study, we attempt to target Arginine auxotrophy in glioblastoma multiforme (GBM) cells using a pegylated recombinant human Arginase I cobalt [HuArgI (Co)-PEG5000]. We tested and characterized the activity of HuArgI (Co)-PEG5000 on a panel of 9 GBM cell lines and on human fetal glial cells (SVG-p12). HuArgI (Co)-PEG5000 was cytotoxic to all GBM cells tested. SVG-p12 cells were not sensitive demonstrating the selective cytotoxicity of HuArgI (Co)-PEG5000-induced arginine deprivation. Addition of l-citrulline led to the rescue of 6 GBM cell lines but only at concentrations of 11.4 mM, reflecting the extent of arginine auxotrophy in GBM. The ability of l-citrulline to rescue cells was dependent on the expression of argininosuccinate synthetase-1 (ASS1) with the cells that were not rescued by l-citrulline being negative for ASS1 expression. Knocking-down ASS1 reversed the ability of l-citrulline to rescue GBM cells, further illustrating the dependence of arginine auxotrophy on ASS1 expression. Inhibition of autophagy increased cell sensitivity to HuArgI (Co)-PEG5000 indicating that, following arginine deprivation, autophagy plays a protective role in GBM cells. Analysis of the type of cell death revealed a lack of AnnexinV staining and caspase activation in HuArgI (Co)-PEG5000-treated cells, indicating that arginine deprivation induces caspase-independent, non-apoptotic cell death in GBM. We have shown that GBM cells are auxotrophic for arginine and can be selectively targeted using HuArgI (Co)-PEG5000-induced arginine depletion, thus demonstrating that l-Arginine deprivation is a potent and selective potential treatment for GBM. en_US
dc.language.iso en en_US
dc.title Human recombinant arginase I (Co)-PEG5000 [HuArgI (Co)-PEG5000]-induced arginine depletion is selectively cytotoxic to human glioblastoma cells en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SAS en_US
dc.author.idnumber 200703859 en_US
dc.author.idnumber 200901419 en_US
dc.author.woa N/A en_US
dc.author.department Natural Sciences en_US
dc.description.embargo N/A en_US
dc.relation.journal Journal of Neuro-Oncology en_US
dc.journal.volume 122 en_US
dc.journal.issue 1 en_US
dc.article.pages 75-85 en_US
dc.keywords HuArgI (Co)-PEG5000 en_US
dc.keywords GBM en_US
dc.keywords Arginine en_US
dc.keywords Autophagy en_US
dc.identifier.doi http://dx.doi.org/10.1007/s11060-014-1698-5 en_US
dc.identifier.ctation Khoury, O., Ghazale, N., Stone, E., El-Sibai, M., Frankel, A. E., & Abi-Habib, R. J. (2015). Human recombinant arginase I (Co)-PEG5000 [HuArgI (Co)-PEG5000]-induced arginine depletion is selectively cytotoxic to human glioblastoma cells. Journal of neuro-oncology, 122(1), 75-85. en_US
dc.author.email mirvat.elsibai@lau.edu.lb
dc.author.email ralph.abihabib@lau.edu.lb
dc.identifier.url http://link.springer.com/article/10.1007/s11060-014-1698-5
dc.orcid.id https://orcid.org/0000-0003-4084-6759 en_US

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