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

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.

• Authors: Leticia Oliveira-Ferrer, Jessica Hauschild, Walter Fiedler, Carsten Bokemeyer, Johannes Nippgen, Ilhan Celik, Gunter Schuch
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 27 Pg. 86 (Dec 29 2008) ISSN: 1756-9966 [Electronic] England
• PMID: 19114005 (Publication Type: Journal Article)

Chemical References

• Actins
• Snake Venoms
• Tumor Suppressor Proteins
• Cilengitide
• Dacarbazine
• DNA Modification Methylases
• MGMT protein, human
• Focal Adhesion Kinase 1
• PTK2 protein, human
• src-Family Kinases
• Oncogene Protein v-akt
• DNA Repair Enzymes
• Temozolomide

Topics

• Actins (metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Adhesion (drug effects)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Cytoskeleton (drug effects, metabolism)
• DNA Methylation
• DNA Modification Methylases (genetics)
• DNA Repair Enzymes (genetics)
• Dacarbazine (administration & dosage, analogs & derivatives)
• Endothelial Cells (drug effects, enzymology, pathology)
• Focal Adhesion Kinase 1 (antagonists & inhibitors, metabolism)
• Glioblastoma (drug therapy, enzymology, genetics, pathology)
• Humans
• Oncogene Protein v-akt (antagonists & inhibitors, metabolism)
• Phosphorylation
• Promoter Regions, Genetic
• Snake Venoms (administration & dosage, pharmacology)
• Swine
• Temozolomide
• Tight Junctions (drug effects)
• Tumor Suppressor Proteins (genetics)
• src-Family Kinases (antagonists & inhibitors, metabolism)