Abstract
Abstract Background: Neuroblastoma is the most common extracranial solid tumor in children, with poor prognosis in children diagnosed after 12-15 months of age. Even with current multimodal therapies, the 5-year event-free survival is below 50%, necessitating the development of new, targeted therapies. Survivin is a developmentally regulated gene that is highly up-regulated in many cancers. In neuroblastoma, survivin is up-regulated by PI3Kinase-AKT signaling and its expression correlates with poor prognosis. Survivin is a member of the Inhibitor of Apoptosis family of proteins and is involved in cell survival through caspase dependent and independent pathways. Knockdown of survivin in melanoma cells reduces cell migration in vitro and its expression correlates with metastasis in Ewing's Sarcoma and Schwann cell tumors. YM155 is a transcriptional suppressor of survivin and has shown efficacy in several cancer model systems both in vivo and in vitro and is currently under clinical investigation for adult cancers. In this study, we investigate the effects of YM155 on neuroblastoma cell apoptosis and migration in vitro and on tumor growth in vivo. Methods: Four neuroblastoma cell lines were treated with YM155 and subject to cell viability and migration assays. Gene expression was investigated by microarray and signaling by Western Blotting. In vivo, effects on tumor volume were determined by xenograft implant of neuroblastoma cell lines followed by YM155 treatment and measurement by calipers. Results: Treatment with YM155 caused a dose-dependent decrease in survivin expression and reduced cell viability in neuroblastoma cell lines; however IC50 values vary by cell line. Cells treated with YM155 near the respective IC50 showed increased cleavage of Caspase 3 and PARP indicating apoptosis. Gene and protein expression changes include reduced CXCR4 and Mcl-1. Low levels of YM155 reduced cell migration by 30-50%; cytotoxicity was not observed at the lower concentrations. Treatment with YM155 reduced tumor growth in vivo by 25-70% and depended on cell line. Conclusions: YM155 inhibits survivin expression, reduces cell viability, induces apoptosis, and migration in vitro, and reduces tumor volume in vivo. Further investigation is warranted in characterization of YM155 as a possible therapeutic agent for neuroblastoma. Citation Format: Heather M. McClung, Ping Zhao, Lauren Smith, Alexandra Eckardt, Giselle L. Sholler. YM155 inhibits survivin-mediated survival, migration, and tumor growth in neuroblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2766. doi:10.1158/1538-7445.AM2013-2766
Published Version
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