Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer but the data remains 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 with significant reductions of survival probability and lung Sirtuin 1 (SIRT1), which has been proposed as a tumor suppressor. The decreased 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 determine whether a xanthophyll beta-cryptoxanthin (BCX), which is associated with a reduced risk of lung cancer from a pooled analysis of seven prospective cohort studies, can inhibit the nicotine-induced emphysema and lung tumorigenesis. We found that BCX supplementation at two different doses reduced 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 lung SIRT1, p53, and rar-beta to the levels of the control group, increased the survival probability, and decreased the lung il-6 mRNA and AKT phosphorylation levels. The present study indicates that the SIRT1 is a potential target for the action of BCX against emphysema and lung cancer. In addition, our study established a relevant animal lung cancer model for studying tumor growth within emphysemateous microenvironments.

Citation Format: Anita Iskandar, Chun Liu, Donald Smith, Kang-Quan Hu, Sang-Woon Choi, Lynne Ausman, Xiang-Dong Wang. Beta-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A37.