The studies proposed here will examine a red marine algae extract for ability to inhibit the outgrowth of abnormal colonic epithelial cells. The source of the extract is the North Atlantic red algae, Lithothamnium coralliodides. The extract is rich in Ca2+ but also contains detectable levels of approximately 70 other minerals. Two pivitol questions will be addressed in this study. First, does the marine algae extract demonstrate efficacy against colonic hyperplasia, colonic polyps and colon carcinoma when used in a 15-month dietary study with genetcally """"""""normal"""""""" mice on a high-fat Western stye diet, and is the extract more effective than inorganic Ca2+ alone? Second, is the extracellular calcium-sensing receptor (CaSR) the critical target for the chemopreventive effects of the algae extract? To address the first question, wild-type (C57bl/6) mice will be maintained for 15 months on a high fat diet that is known to result in the development of multiple colonic polyps and, in some mice, colon cancer (Nemark diet). Some mice on the high fat diet will also receive the algae extract. As controls, other mice will be fed the high fat diet supplemented with inorganic Ca2+ (calcium carbonate). The hypothesis on which the proposed studies are based is that the algae extract will provide more effective colon chemoprevention than inorganic Ca2+ alone. To address the second question, we will assess expression of CaSR in a series of human colon cancer cell lines maintained in the presence or absence of the algae extract. Some of the lines are known to be defective in their response to extracellular Ca2+ alone. We will compare growth arrest and differentiation of the Ca2+ - responsive and non-responsive cells to the marine algae extract. In additional experiments, we will use an siRNA approach to down-regulate CaSR expression in the colon cancer cell lines and determine if CaSR expression is critical for growth inhibition mediated by the algae extract. The results of these experiments will provide insight into cellular and molecular basis of colon cancer chemoprevention by the algae extract and will provide direction for subsequent clinical studies (if warranted).
The overall goals of the studies proposed in this application are to determine if a red marine algae extract that contains detectable levels of up to 70 different minerals has the capacity to suppress abnormal colon epithelial cell growth in mice on a high-fat, Western-style diet, do determine if the high-mineral - containing algae extract is more effective than calcium alone and to determine if the calcium-sensing receptor is the critical target for the growth modulating activities of the algae extract.
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