Chemopreventive Activity of Selenium-Derivatives of Celecoxib in Melanoma

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DESCRIPTION (provided by applicant): This application is submitted in response to a PA entitled "Cancer prevention research small grant program (PAR-06-313)". The primary objective of our proposed studies is to investigate the beneficial chemopreventive effects of a novel combination of selenium (Se), an essential micronutrient, and celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in the development of early melanoma. Malignant melanoma is the most deadly form of skin cancer. While melanoma accounts for roughly 4% of all skin cancers, it is responsible for more than 77% of skin cancer deaths. Thus, novel therapeutic strategies are warranted for the treatment of melanoma as conventional therapies are inefficient. The role of pro-angiogenic prostaglandin E2 (PGE2), which is increased in melanoma, can be mainly attributed to exacerbated expression of COX-2. Based on our previous research, antioxidant Se causes a significant down-regulation of COX-2 expression in a wide range of mammalian cells via the inactivation of the redox-sensitive transcription factor, NF-?B. This could be a key issue in melanoma patients as their plasma levels of Se are significantly reduced. A combinatorial approach that integrates celecoxib and Se into one novel therapeutic compound will be tested for its effect on the proliferation and early development of melanoma by human malignant melanoma cells lines in reconstructed skin models and immunodeficient mice. Studies proposed here are based on the hypothesis that Se supplementation coupled to inhibition of COX-2 expression and activity aids in the retardation of cancerous lesions in experimental models of early melanoma. The hypothesis will be tested in the following Specific Aims: 1) Synthesis of Se-derivatives of celecoxib based on quantitative structure-function analysis of human COX-2 active site; 2) To examine the efficacy of Se-celecoxib derivatives on COX-2 expression/activity and NF-?B activation in human melanoma cell lines, and 3) To examine the chemopreventive effects of Se- celecoxibs on the development of melanoma in the in-vitro reconstructed skin models and their ability to generate subcutaneous tumors in mice. Collectively, preliminary data collected from this program will establish that the central hypothesis is correct and warrants further in-depth research. Studies proposed here will be needed to adequately support the specific aims of a large grant application.