Pharmacological inhibition of Bcl-2 family members reactivates TRAIL-induced apoptosis in malignant glioma
作者： Holger Hetschko , Valerie Voss , Sigrid Horn , Volker Seifert , Jochen H. M. Prehn
DOI: 10.1007/S11060-007-9472-6
关键词:
摘要: The major aim of this study was to develop novel therapeutic approaches potentiate and reactivate apoptosis induced by TNF-Related Apoptosis Inducing Ligand (TRAIL) in malignant glioma. Analysis five glioma cell lines (U87, U251, U373, MZ-54 MZ-18) indicated that only two the were sensitive TRAIL alone. resistance not correlated expression levels death receptors DR4 DR5 or decoy DcR1 DcR2, suggesting it mediated inactivation TRAIL-induced downstream signalling. Activation BH3 protein Bid subsequent activation mitochondrial pathway are known play a pivotal role apoptosis. Since process is blocked overexpression anti-apoptotic Bcl-2 family members, we analyzed potential mimetics potentiating Treatment with combination specific inhibitor HA14-1 Bcl-2/Bcl-xL BH3I-2′ potently enhanced TRAIL-sensitive U87 cells dose-dependent fashion. significantly reactivated one (U343) (MZ-54 three investigated TRAIL-insensitive lines, respectively. Knockdown member Mcl-1 RNA interference had no additional effect on U343 cells. Our data indicate Bcl-xL fundamental roles suggest using agonistic receptor antibodies may represent promising approach therapy-resistant high grade gliomas.
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