Ribavirin as a potential therapeutic for atypical teratoid/rhabdoid tumors
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Joshua Casaos1, Sakibul Huq1, Tarik Lott1, Raphael Felder1, John Choi1, Noah Gorelick1, Michael Peters1, Yuanxuan Xia1, Russell Maxwell1, Tianna Zhao1, Chenchen Ji1, Thomas Simon2, Julie Sesen1,3, Sarah J. Scotland1, Richard E. Kast4, Jeffrey Rubens5, Eric Raabe5, Charles G. Eberhart5, Eric M. Jackson1, Henry Brem1, Betty Tyler1,* and Nicolas Skuli1,3,*
1Hunterian Neurosurgical Research Laboratory, Neurosurgery Department, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA
2Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
3INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, CRCT, 31100 Toulouse, France
4IIAIGC Study Center, Burlington, VT 05401, USA
5Pathology Department, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA
*These authors contributed equally to this work
Betty Tyler, email: [email protected]
Keywords: ribavirin; atypical teratoid/rhabdoid tumor; glioma; therapy; brain tumors
Received: March 09, 2017 Accepted: November 11, 2017 Published: January 03, 2018
Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive, malignant tumors and are the most common malignant brain tumor in children under 6 months of age. Currently, there is no standard treatment for AT/RT. Recent studies have reported potential anti-tumoral properties of ribavirin, a guanosine analog and anti-viral molecule approved by the Food and Drug Administration for treatment of hepatitis C. We previously demonstrated that ribavirin inhibited glioma cell growth in vitro and in vivo. Based on these results and the fact that no pre-clinical model of ribavirin in AT/RT exists, we decided to investigate the effect of ribavirin on several human AT/RT cell lines (BT12, BT16, and BT37) both in vitro and in vivo. We provide evidence that ribavirin has a significant impact on AT/RT cell growth and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E and/or EZH2 pathways. Interestingly, using scratch wound and transwell Boyden chamber assays, we observed that ribavirin also impairs AT/RT cell migration, invasion, and adhesion. Finally, we demonstrate that ribavirin significantly improves the survival of mice orthotopically implanted with BT12 cells. Our work establishes that ribavirin is effective against AT/RT by decreasing tumoral cell growth and dissemination and could represent a new therapeutic option for children with this deadly disease.
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