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Copyright by Eunyoung Park 2007 - The University of Texas at Austin

Copyright by Eunyoung Park 2007 - The University of Texas at Austin

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The PI3K gene is often overexpressed or mutated contributing to tumor progression in breast, colon, and several other cancers [For a review please see: (22)]. In colon cancer, PIK3CA, encoding the p110 subunit, is often mutated in either the kinase domain or helical domain to increase PI3K activity and consequently increase metastasis of colon cancer (23,24). 1.3. Dietary Chemoprevention of Colorectal Cancer The five-year survival rate for colon cancer has dropped for the past 20 years because of improved diagnosis and treatment. However, the five-year survival rate is still 10% for patients whose colorectal cancer metastasized, which indicates the need for more effective therapies to treat colon cancer. Many studies have examined nutrients such as calcium, folate, fiber, omega-3 fatty acids, vitamin D, and vitamin A as prospective chemoprevention and chemotherapy agents for colorectal cancers [For a review please see; (25)]. Fiber has long been considered as a chemoprevention agent for colon cancer. However, intervention randomized trials failed to support the inverse effect of fiber intake on colon cancer prevention (26). However, the other nutrients mentioned above are promising in colon cancer prevention. For example there is an inverse association between calcium and vitamin D intake and risk of colon cancer (27). Calcium and vitamin D may act together to decrease the risk of colorectal cancer, as vitamin D is required for the absorption of calcium. Interestingly, folate showed two opposing effects depending on the stage of colon cancer. Folate supplementation had an inhibitory effect on the initiation of colon cancer progression (28). However, folate 5

deficiency reduced the size of colon cancer lesion (28). Omega-3 fatty acids in fish oil protect against colon tumorigenesis in epidemiologic, preclinical and clinical studies [For a review please see; (29)]. In addition, the retinoids, a group of compounds consisting of vitamin A (retinol), its natural metabolites, and several synthetic compounds have been shown in numerous experimental situations to act as cancer chemopreventive and therapeutic agents [for review see: (30-32)]. All-trans-retinoic acid (ATRA) accomplishes all these activities and most studies concerning retinoids have investigated the mechanisms by which ATRA regulates tumor growth and progression. However, tumors became ATRA-resistant as cancer progresses and the colon is exposed to retinol from the diet. Therefore, we evaluated the antiproliferative, antimetastatic, potentially chemotherapeutic, and chemopreventive effects of dietary vitamin A (retinol) on human colon cancer. 2. RETINOL Retinol (Vitamin A), a fat-soluble vitamin, has important roles in vision, growth and development, immune function, and reproduction. The chemical structure of retinol contains a β-ionone ring, a polyunsaturated tail, and an alcohol end group (Figure 1.2). The diet contains (1) preformed vitamin A as retinyl esters in animal-derived food sources and (2) provitamin A carotenoids in plant-derived food sources. Retinyl esters are cleaved within the intestinal lumen to yield retinol (Figure 1.2). When retinol is absorbed from the enterocytes, retinol is re-esterified and transported to the liver via 6

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