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Cell Cycle, Cell Death, and Senescence

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

Valerie Voss, Christian Senft, Verena Lang, Michael W. Ronellenfitsch, Joachim P. Steinbach, Volker Seifert and Donat Kögel
Valerie Voss
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Christian Senft
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Verena Lang
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Michael W. Ronellenfitsch
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Joachim P. Steinbach
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Volker Seifert
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Donat Kögel
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DOI: 10.1158/1541-7786.MCR-09-0562 Published July 2010
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Abstract

Antiapoptotic Bcl-2 family members suppress both apoptosis and autophagy and are of major importance for therapy resistance of malignant gliomas. To target these molecules, we used BH3 mimetics and analyzed the molecular mechanisms of cell death induced thereby. Glioma cells displayed only limited sensitivity to single-agent treatment with the BH3 mimetics HA14-1, BH3I-2′, and ABT-737, whereas the pan-Bcl-2 inhibitor (−)-gossypol efficiently induced cell death. Furthermore, (−)-gossypol potentiated cell death induced by temozolomide (TMZ) in MGMT (O6-methylguanine-DNA methyltransferase)-negative U343 cells and, to a lesser extent, in MGMT-expressing U87 cells. (−)-Gossypol triggered translocation of light chain 3 to autophagosomes and lysosomes and cytochrome c release, but cell death occurred in the absence of lysosomal damage and effector caspase activation. Lentiviral knockdown of Beclin1 and Atg5 in U87, U343, and MZ-54 cells strongly diminished the extent of cell death induced by (−)-gossypol and combined treatment with TMZ, indicating that autophagy contributed to this type of cell death. In contrast, stable knockdown of the endogenous autophagy inhibitor mammalian target of rapamycin increased autophagic cell death. Our data suggest that pan-Bcl-2 inhibitors are promising drugs that induce caspase-independent, autophagic cell death in apoptosis-resistant malignant glioma cells and augment the action of TMZ. Furthermore, they indicate that efficient killing of glioma cells requires neutralization of Mcl-1. Mol Cancer Res; 8(7); 1002–16. ©2010 AACR.

Footnotes

    • Received December 30, 2009.
    • Revision received May 26, 2010.
    • Accepted May 31, 2010.
    • ©2010 American Association for Cancer Research.
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    Molecular Cancer Research: 8 (7)
    July 2010
    Volume 8, Issue 7
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    The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma
    Valerie Voss, Christian Senft, Verena Lang, Michael W. Ronellenfitsch, Joachim P. Steinbach, Volker Seifert and Donat Kögel
    Mol Cancer Res July 1 2010 (8) (7) 1002-1016; DOI: 10.1158/1541-7786.MCR-09-0562

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    The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma
    Valerie Voss, Christian Senft, Verena Lang, Michael W. Ronellenfitsch, Joachim P. Steinbach, Volker Seifert and Donat Kögel
    Mol Cancer Res July 1 2010 (8) (7) 1002-1016; DOI: 10.1158/1541-7786.MCR-09-0562
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