Cyclooxygenases (COXs: COX-1/-2) and 5-lipoxygenase (5-LOX) catalyzed reactions play significant roles in colon cancer progression. COX inhibitors including ibuprofen, known as non-steroid anti- inflammatory drugs (NSAIDs), have been shown to be effective anticancer agents against colon cancer. However, a critical barrier to utilize the specific inhibitors of these enzymes is associated adverse effects including gastrotoxicity and increased risk of cardiovascular diseases for COX inhibitors. Therefore, we need to search for new prevention and therapeutic strategies that have strong anti-cancer effects with potentially reduced toxicity. We have recently demonstrated that vitamin E forms including 3-tocopherol (3T), 4-tocopherol (4T) and 3-tocotrienol (3TE) are metabolized to long-chain carboxychromanols and their sulfated counterparts in human cells and in rats. Importantly, 13'-carboxychromanol (13'-COOH), the E metabolite containing 13-carbon-length carboxylated side chain, is a potent competitive inhibitor of COX-1/-2 with the potency similar to ibuprofen, while 3T, 4T and 3TE or shorter-side chain carboxychromanols are much weaker COX inhibitors. Our preliminary data indicate that 13'-COOH also inhibited 5-LOX catalyzed leukotriene B4 (LTB4). The dual inhibition of COXs and 5-LOX may not only result in more potent anti-inflammatory and anti-cancer effect (by inhibiting multiple proinflammatory pathways), but may also reduce potential adverse effect caused by a shunt in arachidonate metabolism to either pathway. Therefore, we hypothesize that 13'-COOHs may be excellent anticancer agents. This hypothesis will be tested by pursuit of the following Specific Aims in cell culture and animal studies:1) investigate anti-inflammatory and anticancer activity of 4-13'-COOH (a 13'-COOH derived from 4-tocopherol) in colon epithelial cells and elucidate the mechanism underlying the inhibition of 5-LOX by enzyme kinetics, and 2) investigate in vivo anti-cancer activity of 4-13'-COOH in a mouse model, in which colon carcinogenesis is induced by azoxymethane (AOM) and is accelerated by dextran sulfate sodium (DSS)-caused colon inflammation. The efficacy of 4-13'-COOH will be compared with its unmetabolized precursor 4T and a commonly used NSAID, ibuprofen. The bioavailability and potential adverse effects of 4-13'-COOH during long-term supplementation will also be investigated. The proposed studies may discover a new class of effective anticancer agents, i.e., long-chain carboxychromanols, which may be more effective than NSAIDs and vitamin E forms, and exhibit few adverse effects due to their unique properties. These studies will extend and translate mechanism- based findings to a clinically relevant cancer model and obtain important preclinical data for human clinical studies.
Cyclooxygenases and 5-lipoxygenase catalyzed reactions contribute significantly to the development of colon cancer. We have recently demonstrated that long-chain carboxychromanols, which are novel vitamin E metabolites, potently inhibit cyclooxygenases- and 5-lipoxygenase-mediated reactions. This application is to investigate the anticancer activities of a long-chain carboxychromanol in colon cancer cells and in a colon cancer model in mice. These studies may discover a new class of effective anticancer agents with potentially low toxicity, will extend and translate mechanism-based findings to a clinically relevant animal model, and will gather necessary preclinical data important to human clinical studies.
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