AG488 as a therapy against gliomas
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Jadith Ziegler1,2, Anja Bastian3, Megan Lerner4, Lora Bailey-Downs3, Debra Saunders1, Nataliya Smith1, Jake Sutton1, James D. Battiste5, Michael A. Ihnat3, Aleem Gangjee6 and Rheal A. Towner1,2,3,5
1Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
2Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
3Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
4Department of Surgery Research Laboratory, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
5Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
6Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA
Rheal A. Towner, email: Rheal-Towner@omrf.org
Keywords: gliomas, magnetic resonance imaging (MRI), in vivo, anti-cancer therapy, angiogenesis
Received: February 13, 2017 Accepted: May 05, 2017 Published: May 30, 2017
High-grade gliomas such as glioblastomas (GBM) present a deadly prognosis following diagnosis and very few effective treatment options. Here, we investigate if the small molecule AG488 can be an effective therapy against GBM with both anti-angiogenic as well as an anti-microtubule inhibiting modalities, using a human G55 glioma xenograft model in nude mice. From in vitro studies, we report that AG488 incubation reduced cell viability in G55 and HMEC-1 cells more so than TMZ treatment, and AG488 treatment also decreased cell viability in normal astrocytes, but not as much as for G55 cells (p<0.0001). In vivo investigations indicated that AG488 therapy helped reduce tumor volumes (p<0.0001), prolong survival (p<0.01), increase tumor perfusion (p<0.01), and decrease microvessel density (MVD) (p<0.05), compared to untreated mice or mice treated with non-specific IgG, in the G55 xenograft model. Additionally, AG488 did not induce apoptosis in normal mouse brain tissue. Animal survival and tumor volume changes for AG488 were comparable to TMZ or anti-VEGF therapies, however AG488 was found to be more effective in decreasing tumor-related vascularity (perfusion and MVD). AG488 is a potential novel therapy against high-grade gliomas.
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