Radiotherapy is one of the most widely used cancer treatments, but it is often unsuccessful due to the development of radioresistance by tumor cells and endothelial cells (ECs) lining the tumor blood vessels. We have previously shown that ECs are protected against ionizing irradiation primarily via the activation of the phosphoinositide 3-kinase (PI3 K)-Akt-Bcl-2 survival pathway. Here we report that combination treatment with low doses of PI3 K inhibitor (LY294002), cisplatin and gamma-irradiation resulted in significantly higher (61%) EC death as compared to each agent used alone (17, 17 and 11%, respectively). This combination treatment was equally effective in inducing tumor cell death (72%). Combination treatment also significantly inhibited EC tube formation in Matrigel (75%) as compared to each of the agents used alone (8, 8 and 18% for LY294002, cisplatin and gamma-irradiation, respectively). In our in vivo severe combined immunodeficient mouse model of human tumor growth and angiogenesis, combination treatment with low doses of LY294002, cisplatin and irradiation significantly inhibited the growth of human oral squamous carcinoma (OSCC-3) as well as prostate cancer (LnCap). The combination therapy was also very effective in inhibiting tumor angiogenesis where it showed a greater than 90% decrease in neovascularization. In contrast, combination treatment showed only a 29% inhibition of physiological angiogenesis. Taken together, these results suggest a potentially novel strategy to overcome the resistance in ECs lining tumor blood vessels, thereby enhancing the effectiveness of the radiation and chemotherapy. Moreover, this strategy of using a combination of low doses of PI3K/Akt inhibitor, cisplatin and radiation has the potential of significantly decreasing untoward side effects associated with the maximum tolerated doses of radiation and chemotherapy while maintaining their therapeutic efficacy.