gms | German Medical Science

60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit den Benelux-Ländern und Bulgarien

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

24. - 27.05.2009, Münster

Reactivation of cell death by -/- gossypol in apoptosis-resistant malignant glioma

Meeting Abstract

  • V. Voss - Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt/Main
  • D. Kögel - Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt/Main
  • C. Senft - Klinik und Poliklinik für Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt/Main
  • H. Hetschko - Experimentelle Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt/Main
  • V. Seifert - Klinik und Poliklinik für Neurochirurgie, Johann-Wolfgang-Goethe-Universität, Frankfurt/Main

Deutsche Gesellschaft für Neurochirurgie. 60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit den Benelux-Ländern und Bulgarien. Münster, 24.-27.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. DocP06-09

DOI: 10.3205/09dgnc313, URN: urn:nbn:de:0183-09dgnc3138

Veröffentlicht: 20. Mai 2009

© 2009 Voss et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Objective: Anti-apoptotic Bcl-2 family members play a fundamental role for the therapy resistance of malignant gliomas, and are known to regulate both apoptosis and autophagy. Here, we correlated expression levels of Bcl-2 family members with the inherent cell death resistance of glioma cell lines and compared the efficiency of different small molecule inhibitors of Bcl-2 and Bcl-xL (BH3 mimetics) in reactivating cell death. The mechanisms underlying this reactivation were further investigated with regard to hypoxia tolerance, induction of pro-apoptotic pathways and autophagy.

Methods: Cell death was quantified by FACS analysis of PI/annexin and caspase activity assays. Autophagy was analyzed by translocation of LC3 and FACS analysis of lysosomal activity. Expression analyses were performed by qPCR and Western Blotting. Specific inhibition of Bcl-2 family members was achieved through transient RNA interference, and by the BH3 mimetics HA14-1, BH3I-2´, (-)-gossypol and (±)-gossypol.

Results: Hypoxia-triggered cell death in hypoxia-sensitive MZ-54 glioma cells correlated with mitochondrial dysfunction and autophagy, but occurred in the absence of caspase activation. Inhibition of both Bcl-2 and Bcl-xL with the BH3 mimetics HA14-1 and BH3I-2´ was capable to reactivate anoxia-induced, autophagic cell death in otherwise resistant U343 glioma cells, but failed to induce cell death in the absence of a second death stimulus. In contrast, mono treatment with the pan Bcl-2 inhibitor (-)-gossypol (15 µM) potently induced autophagy and cell death in both cell lines. Efficient concentrations of (-)-gossypol did not exert any cytotoxic effects in non-transformed astrocytes. The effects of gossypol on cell death and autophagy in glioma cells were markedly reduced when racematic (±)-gossypol was applied to the cultures.

Conclusions: Our data reveal that the pan-Bcl-2 inhibitor (-)-gossypol potently induces autophagy and cell death in malignant glioma cells, but not in normal astrocytes. They also support the conjecture that triggering autophagic cell death with (-)-gossypol may represent a reasonable approach for the treatment of apoptosis-resistant malignant gliomas.