TY - JOUR
T1 - Hypoxia enhances the antiglioma cytotoxicity of b10, a glycosylated derivative of betulinic acid
AU - Fischer, Sebastian
AU - Ronellenfitsch, Michael W.
AU - Thiepold, Anna Luisa
AU - Harter, Patrick N.
AU - Reichert, Sebastian
AU - Kögel, Donat
AU - Paschke, Reinhard
AU - Mittelbronn, Michel
AU - Weller, Michael
AU - Steinbach, Joachim P.
AU - Fulda, Simone
AU - Bähr, Oliver
N1 - Funding Information:
MW has received research grants from Antisense Pharma, Bayer, MSD, Merck Serono and Roche, and honoraria for lectures or advisory boards from Antisense Pharma, Magforce, MSD, Merck Serono and Roche. JPS and OB have served as consultants for Roche. OB has recieved a travel grant from Roche. The other authors have no conflicts of interest. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
Funding Information:
The Dr. Senckenberg Institute of Neurooncology is supported by the Dr. Senckenberg Foundation and the Hertie Foundation. J.P.S. is “Hertie Professor of Neurooncology”.
PY - 2014/4/17
Y1 - 2014/4/17
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. Copyright:
AB - 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. Copyright:
UR - http://www.scopus.com/inward/record.url?scp=84899679581&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0094921
DO - 10.1371/journal.pone.0094921
M3 - Article
C2 - 24743710
AN - SCOPUS:84899679581
SN - 1932-6203
VL - 9
JO - PLoS ONE
JF - PLoS ONE
IS - 4
M1 - e94921
ER -