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Title: Beta-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice

Author
item ISKANDAR, ANITA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SMITH, DONALD - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item HU, KANG-QUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item CHOI, SANG-WOON - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item AUSMAN, LYNNE - Tufts University
item WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Cancer Prevention Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/17/2012
Publication Date: 4/6/2013
Citation: Iskandar, A., Liu, C., Smith, D.E., Hu, K., Choi, S., Ausman, L.M., Wang, X. 2013. Beta-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice. Cancer Prevention Research. 6(4):309-320.

Interpretive Summary: Currently there are no dietary components that have been shown to prevent the progression of chronic obstructive pulmonary disease (COPD) and lung cancer. However, the beneficial effect of carotenoid-rich fruits and vegetables against lung cancer risk has been reported in epidemiologic studies. Recently, beta-cryptoxanthin (BCX), a carotenoid found at high levels in citrus fruits (e.g., tangerine and oranges), pumpkins, red peppers, and papayas was identified to be the only carotenoid for which intake was associated with lung cancer risk. In this study we provided the first experimental evidence that BCX at both dietary and supplemental doses significantly decreased cigarette-smoke-related lung inflammation, emphysema and lung cancer in an animal model. The doses of BCX used in this animal study can be achieved by humans by simply consuming 1-3 tangerines daily. This data supports the notion that the beneficial effects of BCX against smoke-related lung diseases are unique and BCX is an effective preventive agent.

Technical Abstract: Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosamino-1-(3-pyridyl)-1-butanone (NNK)-initiated lung cancer in A/J mice. This tumor-promoting effect of nicotine was accompanied by significant reductions in survival probability and lung Sirtuin 1 (SIRT1) expression, which has been proposed as a tumor suppressor. The decreased level of SIRT1 was associated with increased levels of AKT phosphorylation and interleukin (il)-6 mRNA but decreased tumor suppressor p53 and retinoic acid receptor (RAR)-beta mRNA levels in the lungs. Using this mouse model, we then determined whether beta-cryptoxanthin (BCX), a xanthophyll that is strongly associated with a reduced risk of lung cancer in several cohort studies, can inhibit nicotine-induced emphysema and lung tumorigenesis. We found that BCX supplementation at two different doses was associated with reductions of the nicotine-promoted lung tumor multiplicity and volume, as well as emphysema in mice treated with both NNK and nicotine. Moreover, BCX supplementation restored the nicotine-suppressed expression of lung SIRT1, p53, and RAR-beta to that of the control group, increased survival probability, and decreased the levels of lung il-6 mRNA and phosphorylation of AKT. The present study indicates that BCX is a preventive agent against emphysema and lung cancer with SIRT1 as a potential target. In addition, our study establishes a relevant animal lung cancer model for studying tumor growth within emphysematous microenvironments.