Increasing epidemiological evidence supports the role of lycopene as a micronutrient with important health benefits. It appears to provide protection against a broad range of epithelial cancers, including lung, prostate, stomach and colon. However, both the conflicting results of the p-carotene intervention trials in cigarette smokers (which used high doses of p-carotene and increased lung cancer risk) vs. the observational epidemiological studies showing that diets high in fruits and vegetables containing carotenoids (but at much lower concentrations than in the intervention studies) are associated with a decreased risk for lung cancer, and the conflicting results of lycopene effects on lung carcinogenesis in animal studies motivate us to focus our attention on the dosage of lycopene supplementation, biological activities of lycopene and interaction of lycopene metabolism with cigarette smoke. The objective of this investigation is to understand the mechanistic basis for the possible chemopreventive efficacy of lycopene (and its metabolites) against lung cancer development and the metabolic pathway of lycopene under well- controlled experimental conditions, using the ferret model, which is highly analogous to humans. We hypothesize that 1) there is a dose-dependent association between lycopene (or its metabolites) and the prevention (or promotion) of premalignant and malignant lung lesions in smoke-exposed, carcinogen-treated ferrets;2) lycopene (or lycopene metabolites) inhibit lung carcinogenesis by up-regulating insulin-likegrowth factor binding protein-3 (IGFBP-3) as a molecular target and interrupting the signal transduction pathway of IGF-I as a mechanism for the chemopreventive efficacy of lycopene;and 3) both oxidative metabolism of lycopene and expression of carotene 9',10'-monooxygenase (a cleavage enzyme for carotenoids) can be altered by lycopene supplementation and smoke-exposure.
Our specific aims are 1) determine the effectiveness of lycopene (and apo-lO'-lycopenoic acid) in both physiologic (low and median) and pharmacological (high) doses on plasma and tissue levels of lycopene (and apo-lO'-lycopenoic acid), smoke-induced oxidative stress, DNA damage, and development of lung preneoplastic lesions and tumor formation in the carcinogen treated, cigarette smoke-exposed ferrets;2) examine whether the induction of IGFBP-3 with lycopene or its metabolites inhibits the signal transduction pathway of IGF-1 and cell proliferation and promotes apoptosis in both ferret and cell culture models;and 3) investigate the metabolic pathway of lycopene by examining both the expression and activity of carotene 9', lO'-monooxygenase and the formation of apo-lO'-lycopenoids from lycopene in vivo and in vitro. Our research effort will provide important insights regarding the mechanisms leading to the bioactivity of lycopene and its metabolites. This information is critically needed for future human studiesinvolving lycopene for prevention of lung cancer and cancers at other tissue sites. In addition, the establishment of a lung carcinogenesis model in ferrets provides a valuable tool for both lung cancer and carotenoid research fields.

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National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-CDP (01))
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Perloff, Marjorie
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Tufts University
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Ip, Blanche C; Liu, Chun; Lichtenstein, Alice H et al. (2015) Lycopene and apo-10'-lycopenoic acid have differential mechanisms of protection against hepatic steatosis in ?-carotene-9',10'-oxygenase knockout male mice. J Nutr 145:268-76
Ip, Blanche C; Liu, Chun; Ausman, Lynne M et al. (2014) Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice. Cancer Prev Res (Phila) 7:1219-27
Ip, Blanche C; Wang, Xiang-Dong (2014) Non-alcoholic steatohepatitis and hepatocellular carcinoma: implications for lycopene intervention. Nutrients 6:124-62
Ip, Blanche C; Liu, Chun; Smith, Donald E et al. (2014) High-refined-carbohydrate and high-fat diets induce comparable hepatic tumorigenesis in male mice. J Nutr 144:647-53
Melendez-Martinez, Antonio J; Nascimento, Andre F; Wang, Yan et al. (2013) Effect of tomato extract supplementation against high-fat diet-induced hepatic lesions. Hepatobiliary Surg Nutr 2:198-208
Aizawa, Koichi; Liu, Chun; Veeramachaneni, Sudipta et al. (2013) Development of ferret as a human lung cancer model by injecting 4-(Nmethyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Lung Cancer 82:390-6
Iskandar, Anita R; Liu, Chun; Smith, Donald E et al. (2013) ?-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice. Cancer Prev Res (Phila) 6:309-20
Ip, Blanche C; Hu, Kang-Quan; Liu, Chun et al. (2013) Lycopene metabolite, apo-10'-lycopenoic acid, inhibits diethylnitrosamine-initiated, high fat diet-promoted hepatic inflammation and tumorigenesis in mice. Cancer Prev Res (Phila) 6:1304-16
Wang, Xiang-Dong (2012) Lycopene metabolism and its biological significance. Am J Clin Nutr 96:1214S-22S
Chung, Jayong; Koo, Kyeongok; Lian, Fuzhi et al. (2012) Apo-10'-lycopenoic acid, a lycopene metabolite, increases sirtuin 1 mRNA and protein levels and decreases hepatic fat accumulation in ob/ob mice. J Nutr 142:405-10

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