Abstract B73: Screen among 1200 FDA-approved drug library reveals mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme

Abstract

Abstract Glioblastoma multiforme (GBM) is the most aggressive and frequent type of primary brain tumor with dismal survival rates. As GBM cells suppress apoptosis and evade death, re-activating dormant apoptotic programs with pro-apoptotic ligands or small molecules might be a promising approach to direct tumor cells to self-destruct. As such, the tumor-selective killing capacity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) makes it a potential treatment option in GBM. However, many tumor cells are intrinsically resistant and/or acquire resistance to TRAIL. While the mechanisms of TRAIL resistance is still not completely solved, several studies suggest that TRAIL resistance can be overcome by combination therapies. Therefore, combination of TRAIL with secondary chemotherapeutics, radiation or other novel therapeutic drugs might be a favorable therapeutic strategy. In this study, we aimed to identify TRAIL sensitizing agents and utilized a chemical library consisting of 1200 Food and Drug Administration (FDA)-approved compounds in a high-throughput screen that assessed GBM cell viability. In the screen that was conducted in TRAIL-midsensitive and TRAIL-resistant isogenic cell pairs in parallel, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective in reducing cell viability as single agents. Cardiac glycosides constituted a large group among our hits. While cardiac glycosides were potent TRAIL-sensitizers and also singly effective on GBM cells, they caused cell death in non-malignant cells, such as GBM-patient derived fibroblasts. Therefore, the future use of these agents might be challenging due to toxicity problems. We then explored the second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA damaging agent, did not cause any toxicity to non-malignant cells at the doses that were able to synergize with TRAIL on tumor cells. We then investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptor (DR4 and DR5) expression was upregulated markedly, as revealed by qRT-PCR and Western blotting. In addition, we observed significant changes in pro-apoptotic and anti-apoptotic gene expression. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients. Citation Format: Filiz Senbabaoglu, Ahmet Cingöz, Ezgi Kaya, Selena Kazancioglu, Nathan Alan Lack, Ceyda Acilan, Tugba Bagci-Onder. Screen among 1200 FDA-approved drug library reveals mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B73.