MOLECULAR TARGETS OF ANTI-TUMOR NSAIDS

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DESCRIPTION (provided by applicant): Non-steroidal anti-inflammatory drugs (NSAIDs) are attractive candidates for agents that may be useful for the prevention and treatment of cancers. However, their ultimate use will likely be in combination with other therapies. Rational development of combined approaches for chemoprevention or therapy requires an accurate knowledge of the molecular events regulated by the component drugs. The long-term goal of the proposed studies is to enhance the development of anti-tumor NSAIDs for chemoprevention of prostate cancer, by identifying and validating novel molecular targets regulated by these agents. Our studies will focus on R-flurbiprofen (R-FB), an arylpropionic acid derivative with demonstrated chemopreventive activity in prostate cancer models. We have used gene expression profiling to identify R-FB-regulated genes in prostate cancer. These studies have identified CYP24 (= vitamin D 24-hydroxylase) as a gene potently down-regulated by R-FB. The proposed studies will therefore seek to develop further data to characterize the interaction between R-FB and CYP24 regulatory processes. We will specifically seek to 1) characterize R-FB effects on CYP24 regulation and vitamin D receptor expression in prostate epithelial cell lines, through use of standard molecular and cell biology techniques. These studies will identify co-stimulatory signals that can act with 1,25(OH)2 vitamin D3 to promote CYP24 expression, and determine if R-FB can block such signal pathways. 2) We will develop antibodies to allow us to study CYP24 in intact tumors and tissues through immunohistochemistry. Furthermore we will 3) characterize the anti-tumor effects of R-FB in combination with 1,25(OH)2 vitamin D3 using in vitro and in vivo models, to clarify if there are additive or synergistic anti-proliferative effects from these agents. These studies will establish a basis for eventual clinical trials combining anti-tumor NSAIDs such as R-FB, and vitamin D analogues, for the prevention and treatment of malignancies, including prostate cancer.