Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention Cancer Health Disparities Conference 2009
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[Cancer Research 62, 4671-4677, August 15, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

Phosphatidylinositol 3-Kinase/Akt Signaling in the Response of Vascular Endothelium to Ionizing Radiation1

Eric Edwards, Ling Geng, J. Tan, Halina Onishko, Edwin Donnelly and Dennis E. Hallahan2

Departments of Radiation Oncology [E. E., L. G., H. O., D. E. H.] and Radiology [E. D.], Vanderbilt University School of Medicine, and Department of Biomedical Engineering [D. E. H.], Vanderbilt University, Nashville, Tennessee 37232

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.




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Copyright © 2002 by the American Association for Cancer Research.