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

Tagscherer, K E; Fassl, A; Campos, B; Farhadi, M; Kraemer, A; Böck, B C; Macher-Goeppinger, S; Radlwimmer, B; Wiestler, O D; Herold-Mende, C; Roth, W

Tagscherer, K E; Fassl, A; Campos, B; Farhadi, M; Kraemer, A; Böck, B C; Macher-Goeppinger, S; Radlwimmer, B; Wiestler, O D; Herold-Mende, C; Roth, W.

Afiliación

Tagscherer KE; Molecular Neuro-Oncology, German Cancer Research Center, Heidelberg, Germany.

Oncogene ; 27(52): 6646-56, 2008 Nov 06.

Article en En | MEDLINE | ID: mdl-18663354

RESUMEN

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.

Asunto(s)

Apoptosis/efectos de los fármacos; Compuestos de Bifenilo/farmacología; Glioblastoma/metabolismo; Glioblastoma/patología; Nitrofenoles/farmacología; Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores; Sulfonamidas/farmacología; Animales; Línea Celular Tumoral; Glioblastoma/genética; Humanos; Ratones; Células Madre Neoplásicas/citología; Células Madre Neoplásicas/efectos de los fármacos; Piperazinas/farmacología; Unión Proteica; Proteínas Proto-Oncogénicas c-bcl-2/clasificación; Proteínas Proto-Oncogénicas c-bcl-2/genética; Proteínas Proto-Oncogénicas c-bcl-2/metabolismo; Tasa de Supervivencia; Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo; Ensayos Antitumor por Modelo de Xenoinjerto

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Compuestos de Bifenilo / Apoptosis / Glioblastoma / Proteínas Proto-Oncogénicas c-bcl-2 / Nitrofenoles Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2008 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido

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