Abstract 3480: XIAP inhibitors prime glioblastoma cells for γ-irradiation-induced apoptosis and circumvent radioresistance of glioblastoma stem cells

Abstract

Abstract Resistance to radiotherapy remains a major challenge in the treatment of glioblastoma and may be caused by evasion of apoptosis. Since antiapoptotic proteins such as XIAP block apoptosis at the effector phase, XIAP presents a promising target to break radioresistance. In the present study, we therefore investigated the effect of small molecule XIAP inhibitors on radiosensitivity of glioblastoma and corresponding normal cells using glioblastoma cell lines, primary glioblastoma explant cultures, glioblastoma stem cells as well as neurons, glial and neural stem cells. Here, we report that XIAP inhibitors overcome radioresistance of glioblastoma and even target the glioblastoma cancer stem cell population without increasing radiosensitivity of non-malignant cells. XIAP inhibitors significantly enhance γ-irradiation-induced apoptosis in a panel of glioblastoma cell lines. Also, XIAP inhibitors cooperate with γ-irradiation to suppress clonogenic growth of glioblastoma cells demonstrating that the combination treatment affects long-term survival. Analysis of signaling pathways reveals that XIAP inhibitors significantly increase γ-irradiation-triggered loss of mitochondrial membrane potential, cytochrome c release and activation of caspases. Interestingly, inhibition of caspases reduces the cooperative effect of XIAP inhibitors and γ-irradiation to cause mitochondrial perturbations suggesting that XIAP inhibitors initiate a feedback amplification loop back to mitochondria by enhancing caspase activity. By comparison, XIAP inhibition does no alter DNA damage/DNA repair, activation of NF-κB or cell cycle arrest following γ-irradiation indicating that XIAP inhibition has no impact on the initial damage and/or cellular stress response. Of note, XIAP inhibitors also prime patients’ derived, primary glioblastoma cells for γ-irradiation-triggered apoptosis. Since glioblastoma stem cells have recently been implicated in radioresistance of glioblastoma, we also tested the effect of XIAP inhibitors on the cancer stem cell population. Intriguingly, XIAP inhibitors restore sensitivity to γ-irradiation in glioblastoma stem cells that were isolated from fresh glioblastoma surgical specimens. In contrast to malignant cells, XIAP inhibitors alone or in combination with γ-irradiation exert no cytotoxicity on non-transformed cells of the central nervous system including neurons, glial and neural stem cells, pointing to a therapeutic window. Thus, small molecule XIAP inhibitors present a promising new strategy to overcome radioresistance of glioblastoma including glioblastoma stem cells. These findings have important implications for further (pre)clinical evaluation of XIAP inhibitors for radiosensitization of glioblastoma. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3480.