Research

Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway

Leticia Oliveira-Ferrer¹ , Jessica Hauschild¹ , Walter Fiedler¹ , Carsten Bokemeyer¹ , Johannes Nippgen² , Ilhan Celik² and Gunter Schuch¹

¹  Department of Oncology and Hematology with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

²  Merck Serono, Darmstadt, Germany

author email corresponding author email

Journal of Experimental & Clinical Cancer Research 2008, 27:86doi:10.1186/1756-9966-27-86

Published:	29 December 2008

Abstract

Background

The antiangiogenic agent cilengitide disrupts integrin binding to the extracellular matrix leading to apoptosis of activated endothelial cells. Integrins are also widely expressed in malignant glioma and integrin inhibitors may directly target tumor cells in this disease. Aim of the current study was to investigate effects of cilengitide on endothelial and glioma cells on molecular and cellular levels.

Results

Cilengitide caused dose-dependent detachment of endothelial cells from cell culture dishes. Proliferation of endothelial cells was significantly inhibited while the proportion of apoptotic cells was increased. Incubation of integrin-expressing glioma cells with cilengitide caused rounding and detachment after 24 hours as observed with endothelial cells. Cilengitide inhibited proliferation and induced apoptosis in glioma cells with methylated MGMT promotor when given alone or in combination with temozolomide. In endothelial as well as glioma cells cilengitide inhibited phosphorylation of FAK, Src and Akt. Assembly of cytoskeleton and tight junctions was heavily disturbed in both cell types.

Conclusion

Cilengitide inhibits integrin-dependent signaling, causes disassembly of cytoskeleton, cellular detachment and induction of apoptosis in endothelial and glioma cells thereby explaining the profound activity of integrin inhibitors in gliomas. The combination of cilengitide with temozolomide exerted additive effects in glioma cells as observed clinically.