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

Alok R. Singh, Shweta Joshi, Elizabeth George, Donald L. Durden

Research output: Contribution to journalArticle

12 Scopus citations

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 V12 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.

Original languageEnglish (US)
Article number105
JournalCancer Cell International
Volume14
Issue number1
DOIs
StatePublished - 2014

Keywords

  • EGF
  • Migration
  • Proliferation
  • SF1126
  • V-Ha-Ras-astrocytoma cells
  • Xenograft model
  • aß integrin

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

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