Molecular Modulation of Inhibitors of Apoptosis as a Novel Approach for Radiosensitization of Human Prostate Cancer

摘要

The major goal of the project is to investigate the radiosensitization activity and mechanism of action of novel IAP-inhibitors in prostate cancer. In the third year of the project, we have investigated the in vivo radiosensitization activity of our lead IAPinhibitors, SH-130 and Embelin, and mechanism of action in human prostate cancer xenograft model. IAP- inhibitors potently enhanced radiation-induced tumor growth inhibition, together with increased induction of apoptosis. In nude mouse xenograft models, IAP-inhibitors Embelin and SH-130 potently sensitized the DU-145 tumors to X- ray radiation. Mechanism studies show that NK-kB pathway activation was also inhibited in the combination therapy. Interestingly, we also observed anti- angiogenic effect of the combination treatment. Due to the lab move in March, 2008, together with our animal room moved and more importantly the move of our X-ray irradiator at the same time, our animal experiments were delayed. We have requested and obtained approval a one year no-cost extension for finish the planned animal and MOA studies.