Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation.

Edwards E, Geng L, Tan J, Onishko H, Donnelly E, Hallahan DE
Cancer Res. 2002 62 (16): 4671-7

PMID: 12183424

Growth factor enhancement of endothelial cell viability occurs through phosphatidylinositol 3-kinase (PI3K)/Akt-mediated inhibition of apoptosis. The PI3K/Akt signal transduction pathway was activated by both vascular endothelial growth factor and ionizing radiation. Radiation- and vascular endothelial growth factor-induced phosphorylation of Akt was inhibited by PI3K antagonists. To determine whether this signal transduction pathway represents a therapeutic target in tumor vascular endothelium, we examined the effects of the PI3K inhibitors wortmannin and LY294002 on irradiated endothelium. Wortmannin and LY294002 enhanced radiation-induced apoptosis and cytotoxicity in endothelial cells. Tumor vascular window and Doppler ultrasound showed that PI3K antagonists enhanced radiation-induced destruction of tumor blood vessels. Tumor growth delay was significantly increased after treatment with LY294002 followed by irradiation as compared with either agent alone. PI3K in tumor vascular endothelium is a potential therapeutic target to enhance the efficacy of ionizing radiation.

MeSH Terms (20)

Androstadienes Animals Apoptosis Cells, Cultured Cell Survival Chromones Endothelium, Vascular Enzyme Inhibitors Glioblastoma Humans Mice Mice, Inbred C57BL Morpholines Phosphatidylinositol 3-Kinases Phosphorylation Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Signal Transduction Wortmannin

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