A Novel Compound Targeting Protease Receptor 1 Activators for the Treatment of Glioblastoma
| Autor: | Efrat Shavit-Stein, Ehud Sheinberg, Valery Golderman, Shirley Sharabi, Anton Wohl, Shany Guly Gofrit, Zion Zivli, Natalia Shelestovich, David Last, David Guez, Dianne Daniels, Orna Gera, Kate Feingold, Zeev Itsekson-Hayosh, Nurit Rosenberg, Ilia Tamarin, Amir Dori, Nicola Maggio, Yael Mardor, Joab Chapman, Sagi Harnof |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Frontiers in Neurology, Vol 9 (2018) |
| Druh dokumentu: | article |
| ISSN: | 1664-2295 17859433 |
| DOI: | 10.3389/fneur.2018.01087 |
| Popis: | Data from human biopsies, in-vitro and in-vivo models, strongly supports the role of thrombin, and its protease-activated receptor (PAR1) in the pathology and progression of glioblastoma (GBM), a high-grade glial tumor. Activation of PAR1 by thrombin stimulates vasogenic edema, tumor adhesion and tumor growth. We here present a novel six amino acid chloromethyl-ketone compound (SIXAC) which specifically inhibits PAR1 proteolytic activation and counteracts the over-activation of PAR1 by tumor generated thrombin. SIXAC effects were demonstrated in-vitro utilizing 3 cell-lines, including the highly malignant CNS-1 cell-line which was also used as a model for GBM in-vivo. The in-vitro effects of SIXAC on proliferation rate, invasion and thrombin activity were measured by XTT, wound healing, colony formation and fluorescent assays, respectively. The effect of SIXAC on GBM in-vivo was assessed by measuring tumor and edema size as quantified by MRI imaging, by survival follow-up and brain histopathology. SIXAC was found in-vitro to inhibit thrombin-activity generated by CNS-1 cells (IC50 = 5 × 10−11M) and significantly decrease proliferation rate (p < 0.03) invasion (p = 0.02) and colony formation (p = 0.03) of these cells. In the CNS-1 GBM rat animal model SIXAC was found to reduce edema volume ratio (8.8 ± 1.9 vs. 4.9 ± 1, p < 0.04) and increase median survival (16 vs. 18.5 days, p < 0.02 by Log rank Mental-Cox test). These results strengthen the important role of thrombin/PAR1 pathway in glioblastoma progression and suggest SIXAC as a novel therapeutic tool for this fatal disease. |
| Databáze: | Directory of Open Access Journals |
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