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57th Annual Meeting of the German Society of Neurosurgery
Joint Meeting with the Japanese Neurosurgical Society

German Society of Neurosurgery (DGNC)

11 - 14 May, Essen

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Target-specific reactivation of apoptosis pathways in malignant glioma

Targetspezifische Reaktivierung der Apoptose bei malignen Gliomen

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  • corresponding author D. Kögel - Klinik für Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität Frankfurt/Main
  • H. Hetschko - Klinik für Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität Frankfurt/Main
  • S. Horn - Neurochirurgische Klinik, Johannes-Gutenberg-Universität Mainz
  • J. Weissenberger - Klinik für Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität Frankfurt/Main

Deutsche Gesellschaft für Neurochirurgie. Japanische Gesellschaft für Neurochirurgie. 57. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie. Essen, 11.-14.05.2006. Düsseldorf, Köln: German Medical Science; 2006. DocP 05.66

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/dgnc2006/06dgnc283.shtml

Published: May 8, 2006

© 2006 Kögel et al.
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Outline

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Objective: The oxygenation status of solid tumors is negatively correlated with their resistance against antineoplastic treatment. The purpose of this study was to elucidate dysfunctions in the intrinsic and extrinsic apoptosis pathways in hypoxia- and therapy-resistant glioblastoma multiforme (GBM) cell lines and to identify suitable targets to reactivate apoptosis in GBM.

Methods: Established GBM cell lines A172, U87, U251, U343 and U373, and a set of thirteen cell lines derived from patients with grade IV astrocytomas were examined for apoptosis sensitivity. Cell death induced by hypoxia (≤0.1% O2), recombinant TRAIL and chemical inhibitors of Bcl-2/Bcl-xL was quantified by FACS analysis of annexin-V and propidium iodide stained cells. Mitochondrial dysfunction was analyzed by FACS analysis of TMRM fluorescence. Differential gene expression profiles of GBM cell lines were obtained with DNA microarrays.

Results: Quantification of cell death revealed drastic differences in the sensitivity of different GBM cell lines to hypoxia and TRAIL. In contrast to TRAIL, hypoxia-induced cell death was independent of caspase-3 activation, but was associated with a potent decrease of the mitochondrial membrane potential (ΔΨm) in the sensitive cell lines. Further analyses indicated no correlation between hypoxia-induced activation of the putative tumor suppressors and pro-apoptotic proteins BNip3 and BNip3L/Nix and hypoxia-sensitivity. However, differential expression profiles, semiquantitative RT-PCR and Western blot analyses revealed aberrant expression of several regulators of the mitochondrial pathway of apoptosis. Synthetic inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL potentiated hypoxia-induced cell death in hypoxia-responding cell lines and synergistically enhanced cell death in combination with TRAIL treatment in the TRAIL-sensitive cell lines.

Conclusions: Multiple dysfunctions in the intrinsic and extrinsic apoptosis pathways contribute to hypoxia and therapy resistance in GBM cell lines. Treatment with small-molecule Bcl-2 and Bcl-xL antagonists in combination with the death receptor ligand TRAIL could be a promising therapy approach to reactivate apoptosis in a subset of GBMs in the future.