Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins

被引:0
|
作者
K E Tagscherer
A Fassl
B Campos
M Farhadi
A Kraemer
B C Böck
S Macher-Goeppinger
B Radlwimmer
O D Wiestler
C Herold-Mende
W Roth
机构
[1] Molecular Neuro-Oncology,Division of Neurosurgical Research, Department of Neurosurgery
[2] German Cancer Research Center,Division of Molecular Genetics
[3] University of Heidelberg,undefined
[4] Institute of Pathology,undefined
[5] University of Heidelberg,undefined
[6] German Cancer Research Center,undefined
来源
Oncogene | 2008年 / 27卷
关键词
apoptosis; brain tumors; glioma; ABT-737; Bcl-2 inhibitor;
D O I
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中图分类号
学科分类号
摘要
Defects in the apoptotic signaling cascades contribute to the poor therapeutic response of malignant gliomas. As glioblastomas are characterized by high expression levels of anti-apoptotic Bcl-2 family proteins, we studied the effects of the novel Bcl-2 inhibitor, ABT-737, on malignant glioma cells. ABT-737 treatment released the pro-apoptotic Bax protein from its binding partner Bcl-2 and potently induced apoptotic cell death in glioblastoma cells in vitro and in vivo. The local administration of ABT-737 prolonged the survival in an intracranial glioma xenograft model. Downregulation of Mcl-1 and overexpression of Bcl-2 sensitized the cells to ABT-737-mediated apoptosis. Moreover, ABT-737 potentiated the cytotoxicity of the chemotherapeutic drugs vincristine and etoposide, and of the death ligand TRAIL. As glioma stem cells may play a crucial role for the tumor progression and the resistance to treatment in glioblastomas, we investigated the effects of ABT-737 on the subpopulation of glioma cells exhibiting stem cell characteristics. Inhibition of proliferation and induction of apoptosis by ABT-737 were less efficient in glioma stem cells than in non-stem cell-like glioma cells. As the resistance of glioma stem cells was associated with high Mcl-1 expression levels, ABT-737 treatment combined with downregulation of Mcl-1 could represent a promising novel approach in glioblastoma treatment.
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页码:6646 / 6656
页数:10
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