Document Detail


BH3 mimetics reactivate autophagic cell death in anoxia-resistant malignant glioma cells.
MedLine Citation:
PMID:  18670645     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Here, we investigated the specific roles of Bcl-2 family members in anoxia tolerance of malignant glioma. Flow cytometry analysis of cell death in 17 glioma cell lines revealed drastic differences in their sensitivity to oxygen withdrawal (<0.1% O(2)). Cell death correlated with mitochondrial depolarization, cytochrome C release, and translocation of green fluorescent protein (GFP)-tagged light chain 3 to autophagosomes but occurred in the absence of caspase activation or phosphatidylserine exposure. In both sensitive and tolerant glioma cell lines, anoxia caused a significant up-regulation of BH3-only genes previously implicated in mediating anoxic cell death in other cell types (BNIP3, NIX, PUMA, and Noxa). In contrast, we detected a strong correlation between anoxia resistance and high expression levels of antiapoptotic Bcl-2 family proteins Bcl-xL, Bcl-2, and Mcl-1 that function to neutralize the proapoptotic activity of BH3-only proteins. Importantly, inhibition of both Bcl-2 and Bcl-xL with the small-molecule BH3 mimetics HA14-1 and BH3I-2' and by RNA interference reactivated anoxia-induced autophagic cell death in previously resistant glioma cells. Our data suggest that endogenous BH3-only protein induction may not be able to compensate for the high expression of antiapoptotic Bcl-2 family proteins in anoxia-resistant astrocytomas. They also support the conjecture that BH3 mimetics may represent an exciting new approach for the treatment of malignant glioma.
Authors:
Holger Hetschko; Valerie Voss; Christian Senft; Volker Seifert; Jochen H M Prehn; Donat Kögel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  10     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-01     Completed Date:  2008-10-20     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  873-85     Citation Subset:  IM    
Affiliation:
Department of Neurosurgery, Johann Wolfgang Goethe University Clinics, Frankfurt, Main, Germany.
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MeSH Terms
Descriptor/Qualifier:
Benzamides / pharmacology*
Benzopyrans / pharmacology*
Biomimetic Materials / pharmacology*
Caspases / metabolism
Cell Death / drug effects
Cell Hypoxia / drug effects
Drug Resistance, Neoplasm
Flow Cytometry
Glioma / drug therapy,  metabolism*,  pathology
Humans
Membrane Potential, Mitochondrial
Microscopy, Fluorescence
Nitriles / pharmacology*
Proto-Oncogene Proteins c-bcl-2 / drug effects,  metabolism*
RNA Interference / drug effects
RNA, Small Interfering / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Sensitivity and Specificity
Tumor Cells, Cultured
Up-Regulation / drug effects
bcl-2-Associated X Protein / drug effects,  metabolism
bcl-X Protein / drug effects,  metabolism
Chemical
Reg. No./Substance:
0/3-iodo-5-chloro-N-(2-chloro-5-((4-chlorophenyl)sulphonyl)phenyl)-2-hydroxybenzamide; 0/BAX protein, human; 0/BCL2L1 protein, human; 0/Benzamides; 0/Benzopyrans; 0/Nitriles; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Small Interfering; 0/bcl-2-Associated X Protein; 0/bcl-X Protein; 0/ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; 0/myeloid cell leukemia sequence 1 protein; EC 3.4.22.-/Caspases
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