Anti-tumor effect of a novel PI3-kinase inhibitor, SF1126, in (12) V-Ha-Ras transgenic mouse glioma model.

ABSTRACT

BACKGROUND: Growth factor mediated activation of RAS-MAP-kinase and PI3-kinase-AKT pathways are critical for the pathogenesis of glioblastoma. The attenuation of PI3-kinase/AKT signaling will be effective in regulating the tumorigenic phenotypes of the glioma cells. METHODS: Glioma cells derived from the brain of the (12) V-Ha-Ras transgenic mice were used to study the effect of PI-3 kinase inhibitor SF1126 on activation of AKT and ERK signaling, proliferation, vitronectin mediated migration and changes in the distribution of cortical actin on vitronectin in the glioma cells in vitro. The anti-tumor effects of SF1126 were also tested in vivo using pre-established tumors (subcutaneous injection of the glioma cells from (12) V-Ha-Ras transgenic mice) in a mouse xenograft model. RESULTS: Our results demonstrate that treatment of LacZ+, GFAP + and PCNA + (12) V-Ras Tg transformed astrocytes with SF1126 and LY294002 blocked the activation of AKT as well as EGF-induced phospho-ERK. Most notably, treatment of SF1126 blocked integrin-dependent migration in transwell and scratch assays and caused a significant change in the organization and distribution of cortical actin on vitronectin in the glioma cells. Moreover, SF1126 treatment inhibited in vitro proliferation of these cells and in vivo growth of pre-established subcutaneous tumors in a xenograft model. CONCLUSION: The present study validate the potent anti-proliferative and anti-migratory activity of SF1126, in a V(12) Ras oncogene driven glioma model and suggest that this effect is mediated potentially through a combined attenuation of PI3-kinase and MAP-kinase signaling pathways.