Abstract
Abstract Glioblastoma multiforme (GBM) is the most common form of primary brain tumor and often characterized by poor survival. Glioblastoma initiating cells (GICs) regulate self-renewal, differentiation and tumor initiation properties, and are involved in tumor growth, recurrence, and resistance to conventional treatments. The objectives of this study were to examine the molecular mechanisms by which inhibition of PI3K/mTOR and Sonic hedgehog (Shh) pathways cooperate together to suppress GIC growth in vitro and in vivo. PI3K/mTOR and Shh pathways were inhibited by NPV-LDE-225 (Erismodegib) and BEZ-235, respectively. Cell viability and apoptosis were measured by XTT and annexin/IV-PI assays, respectively. Gli transcriptional activity was measured by luciferase reporter assay. Gene and protein expressions were measured by qRT-PCR and Western blot analyses, respectively. NPV-LDE-225 inhibited Gli1 and Gli2 expression and transcription activity. BEZ-235 inhibited the phosphorylation of PI3K and mTOR. NPV-LDE-225 and BEZ-235 acted in a synergistic manner to inhibit cell viability, neurosphere formation, and Gli transcriptional activity, and to induce apoptosis by activation of caspase-3 and cleavage of PARP. Furthermore, NPV-LDE-225 and BEZ-235 cooperates together to inhibit pluripotency maintaining factors (Nanog, Oct4, Sox-2, and cMyc) and epithelial-mesenchymal transition. Finally, the interactive effects of NPV-LDE-225 and BEZ-235 on GIC tumor growth in nude mice was higher than single agent alone. Our data suggest that the combined inhibition of PI3K/mTOR and smoothened can be used for the treatment of GBM by targeting GICs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A189. Citation Format: Narinder Sharma, Dhruv Kumar, Yiming Ma, Wei Yu, Sharmila Shankar, Rakesh K. Srivastava. The combination of NPV-LDE-225 (Erismodegib) and BEZ-235 is superior to single agent alone in inhibiting glioblastoma initiating cell growth in vitro and in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A189.
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