TY - JOUR A1 - Fischer, Sebastian A1 - Ronellenfitsch, Michael Wilfried A1 - Thiepold, Anna-Luisa A1 - Harter, Patrick Nikolaus A1 - Reichert, Sebastian A1 - Kögel, Donat A1 - Paschke, Reinhard A1 - Mittelbronn, Michel Guy André A1 - Weller, Michael A1 - Steinbach, Joachim Peter A1 - Fulda, Simone A1 - Bähr, Oliver T1 - Hypoxia enhances the antiglioma cytotoxicity of b10, a glycosylated derivative of betulinic acid T2 - PLoS One N2 - B10 is a glycosylated derivative of betulinic acid with promising activity against glioma cells. Lysosomal cell death pathways appear to be essential for its cytotoxicity. We investigated the influence of hypoxia, nutrient deprivation and current standard therapies on B10 cytotoxicity. The human glioma cell lines LN-308 and LNT-229 were exposed to B10 alone or together with irradiation, temozolomide, nutrient deprivation or hypoxia. Cell growth and viability were evaluated by crystal violet staining, clonogenicity assays, propidium iodide uptake and LDH release assays. Cell death was examined using an inhibitor of lysosomal acidification (bafilomycin A1), a cathepsin inhibitor (CA074-Me) and a short-hairpin RNA targeting cathepsin B. Hypoxia substantially enhanced B10-induced cell death. This effect was sensitive to bafilomycin A1 and thus dependent on hypoxia-induced lysosomal acidification. Cathepsin B appeared to mediate cell death because either the inhibitor CA074-Me or cathepsin B gene silencing rescued glioma cells from B10 toxicity under hypoxia. B10 is a novel antitumor agent with substantially enhanced cytotoxicity under hypoxia conferred by increased lysosomal cell death pathway activation. Given the importance of hypoxia for therapy resistance, malignant progression, and as a result of antiangiogenic therapies, B10 might be a promising strategy for hypoxic tumors like malignant glioma. Y1 - 2014 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/33613 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-336132 SN - 1932-6203 N1 - Copyright: © 2014 Fischer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. VL - 9 IS - (4):e94921 PB - PLoS CY - Lawrence, Kan. ER -