Enhancing Effect of Radiation Therapy Using Non-Steroidal Anti- Inflammatory Agents

摘要

Our earlier studies demonstrated that ibuprofen sensitizes prostate carcinoma cells to radiation in vitro and in vivo. The cytotoxic and radiosensitizing effects of ibuprofen were seen at much higher concentration than that required to inhibit prostaglandin synthesis. To understand the molecular mechanisms involved in radiosensitization we examined the effects of ibuprofen on several potential cellular targets including COX-2 and transcription factor NFkB. COX-2 was constitutively expressed in PC3 cells and was further upregulated by NSAIDs. Ibuprofen inhibited constitutive as well as cytokine-' or radiation-activated NFkB in prostate cancer cells. Currently we are evaluating the effect of ibuprofen on hypoxia-induced expression of the angiogenic factor HIF-lalpha and the subsequent VEGF secretion. HIF-lalpha protein is constitutively expressed in prostate cancer cell lines under normoxic condition and is significantly upregulated by hypoxia. Ibuprofen inhibited HIF- lalpha under normoxic condition but was less effective under hypoxic condition. Ibuprofen inhibited VEGF protein under nonnoxic and hypoxic condition. We are also evaluating the effects of other NSAIDs that selectively inhibit COX-2 and have proven to be less toxic in clinic. The results from this research project can be directly translated into the clinic with a potential to improve local tumor control, to reduce toxicity and increase overall survival.