The
phosphatidylinositol 3'-kinase (PI3k)/
protein kinase B (PKB/Akt) signal transduction pathway plays a critical role in mediating endothelial cell survival and function during oxidative stress. The role of the PI3k/Akt signaling pathway in promoting cell viability was studied in vascular endothelial cells treated with ionizing radiation. Western blot analysis showed that Akt was rapidly phosphorylated in response to radiation in primary culture endothelial cells (human umbilical vascular endothelial cells) in the absence of serum or
growth factors. PI3k consists of p85 and p110 subunits, which play a central upstream role in Akt activation in response to exogenous stimuli. The delta
isoform of the p110 subunit is expressed in endothelial cells. We studied the effects of the p110delta specific inhibitor
IC486068, which abrogated radiation-induced phosphorylation of Akt.
IC486068 enhanced radiation-induced apoptosis in endothelial cells and reduced cell migration and tubule formation of endothelial cells in
Matrigel following irradiation. In vivo
tumor growth delay was studied in mice with
Lewis lung carcinoma and GL261 hind limb
tumors. Mice were treated with daily i.p.
injections (25 mg/kg) of
IC486068 during 6 days of
radiation treatment (18 Gy). Combined treatment with
IC486068 and radiation significantly reduced
tumor volume as compared with either treatment alone. Reduction in vasculature was confirmed using the dorsal skinfold vascular window model. The vascular length density was measured by use of the
tumor vascular window model and showed
IC486068 significantly enhanced radiation-induced destruction of
tumor vasculature as compared with either treatment alone.
IC486068 enhances radiation-induced endothelial cytotoxicity, resulting in
tumor vascular destruction and
tumor control when combined with fractionated
radiotherapy in murine
tumor models. These findings suggest that p110delta is a therapeutic target to enhance radiation-induced
tumor control.