Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation.
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.
Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Eric
E
Edwards
Ling
L
Geng
J
J
Tan
Halina
H
Onishko
Edwin
E
Donnelly
Dennis E
DE
Hallahan
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology / Q000528:radiation effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000528:radiation effects; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human