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.
机构:
Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USADana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
Schlis, Krysta D.
Sallan, Stephen E.
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Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USADana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
Sallan, Stephen E.
Armstrong, Scott A.
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Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USADana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
机构:
Univ Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, France
Univ Paris Saclay, Inst Gustave Roussy, INSEAM 1279, F-94805 Villejuif, FranceUniv Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, France
Robert, Aude
Pujals, Anais
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Univ Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, France
Univ Paris Est Creteil, CHU Henri Mondor, AP HP, Inserm,U955,Dept Pathol, Creteil, FranceUniv Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, France
Pujals, Anais
Favre, Loetitia
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Univ Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, France
Univ Paris Est Creteil, CHU Henri Mondor, AP HP, Inserm,U955,Dept Pathol, Creteil, FranceUniv Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, France
Favre, Loetitia
Debernardi, Justine
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Univ Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, FranceUniv Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, France
Debernardi, Justine
Wiels, Joelle
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Univ Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, FranceUniv Paris Saclay, Inst Gustave Roussy, UMR 8126, CNRS, Villejuif, France