Small-molecule XIAP inhibitors enhance γ-irradiation-induced apoptosis in glioblastoma

Sri Hari Krishna Vellanki, Andreas Grabrucker, Stefan Liebau, Christian Proepper, Adriana Eramo, Veit Braun, Tobias Boeckers, Klaus Michael Debatin, Simone Fulda

Research output: Contribution to journalArticlepeer-review

Abstract

Because evasion of apoptosis can cause radioresistance of glioblastoma, there is a need to design rational strategies that counter apoptosis resistance. In the present study, we investigated the potential of targeting the antiapoptotic protein XIAP for the radiosensitization of glioblastoma. Here, we report that small-molecule XIAP inhibitors significantly enhance γ-irradiation-induced loss of viability and apoptosis and cooperate with γ-irradiation to suppress clonogenic survival of glioblastoma cells. Analysis of molecular mechanisms reveals that XIAP inhibitors act in concert with γ-irradiation to cause mitochondrial outer membrane permeabilization, caspase activation, and caspasedependent apoptosis. Importantly, XIAP inhibitors also sensitize primary cultured glioblastoma cells derived from surgical specimens as well as glioblastoma-initiating stemlike cancer stem cells for γ-irradiation. In contrast, they do not increase the toxicity of γ-irradiation on some nonmalignant cells of the central nervous system, including rat neurons or glial cells, pointing to some tumor selectivity. In conclusion, by demonstrating for the first time that smallmolecule XIAP inhibitors increase the radiosensitivity of glioblastoma cells while sparing normal cells of the central nervous system, our findings build the rationale for further (pre)clinical development of XIAP inhibitors in combination with γ-irradiation in glioblastoma.

Original languageEnglish
Pages (from-to)743-752
Number of pages10
JournalNeoplasia
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 2009
Externally publishedYes

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