Abstract 3877: ABT-737 synergizes with bortezomib to induce apoptosis: Activation of Bid, Bak, and Bax in the apoptotic response in malignant human glioma cells

Abstract

Abstract Glioblastomas are invasive tumors with poor prognosis despite current therapies. ABT-737 has monotherapeutic toxicity against leukemia, lymphoma and other malignancies, and we and others have noted some antiglioma activity, although insufficient to warrant use as monotherapy. We have recently demonstrated that proteasome inhibitors, such as bortezomib, dramatically sensitized highly resistant glioma cells to apoptosis induction, suggesting that proteasomal inhibition may be a promising combination strategy for glioma therapeutics. In this study, we examined whether bortezomib could enhance response to ABT-737 inhibition in glioma cells. Although primary cells from glioblastoma multiforme (GBM) patients and established glioma cell lines did not show significant induction of apoptosis with ABT-737 treatment alone, the combination of ABT-737 plus bortezomib, significantly enhanced apoptosis. The enhanced efficacy was due to proapoptotic mitochondrial injury and increased generation of reactive oxygen species. Our results also revealed that combination of bortezomib/ABT-73 enhanced apoptosis by increasing Bid cleavage, Noxa upregulation, Bak, Bax activation, and cytochrome c release. Further downregulation of Mcl-1 using shRNA enhanced cell killing by the bortezomib/ABT-737 combination. The significantly enhanced antitumor activity that results from the combination of bortezomib and ABT-737 offers promise as a novel treatment for glioma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3877. doi:1538-7445.AM2012-3877