The anti-carcinogenic effect of carotenoids against lung cancer

Beneficial effects of carotenoid-rich fruits and vegetables on lung cancer risk have been found in numerous observational studies. However, recent studies have suggested that carotenoids other than beta-carotene in fruits and vegetables, such as lycopene, a major carotenoid in tomato and tomato-based products, and beta-cryptoxanthin, a carotenoid in orange juice, may, play a role in the reduction of lung cancer risk.; The chemopreventive effect of lycopene against lung cancer has been demonstrated in many epidemiological studies and animal studies. Although its mechanisms are not well defined, it has been suggested that the chemopreventive activity of lycopene against cancers may partly be mediated by its metabolites. In this project, we demonstrated apo-10'-lycopenoic acid inhibited the growth of cell derived from normal lung or lung cancer in dose- and time-dependent manners, blocked cell cycle progression in G1 phase, decreased cyclin E and increased p21 and p27 protein levels. In addition, apo-10'-lycopenoic acid increased the mRNA levels of retinoic acid target genes, RARbeta and IGFBP-3. Furthermore, apo-10'-lycopenoic acid transactivated RARbeta promoter-driven luciferase activity in a RARE-dependent manner, suggesting that apo-10'-lycopenoic acid functions through a retinoic acid signaling pathway. These anti-carcinogenic effects of apo-10'-lycopenoic acid against lung cancer support the notion that certain biological functions of lycopene are mediated by its metabolites. We further investigated the chemopreventive effect of apo-10'-lycopenoic acid supplementation against 4-(N-methyl-N-nitrosamino)-1-(3-pyridal)-1-butanone (NNK)-induced lung cancers in the A/J mouse model. The results showed that NNK-induced lung tumor multiplicity was decreased dose-dependently in mice given apo-10'-lycopenoic acid supplementation, as compared with the mice given NNK alone. This protective effect of apo-10'-lycopenoic acid was associated with an increase in p27 protein in the lung tissues of mice. These data suggest that the preventive effect of lycopene against lung cancer is, at least in part, mediated by its metabolites, and that apo-10'-lycopenoic acid may be a useful chemopreventive agent against lung carcinogenesis.; beta-Cryptoxanthin is inversely associated with lung cancer risk in epidemiologic studies. In this project, we showed that beta-cryptoxanthin inhibited the growth of both premalignant and malignant lung cells in a dose-dependent manner. beta-Cryptoxanthin suppressed protein levels of cyclin D1 and cyclin E, up-regulated the cell cycle inhibitor p21, and blocked cell cycle progress in G1/G0 phase. In addition, beta-cryptoxanthin induced mRNA levels of RARbeta, which is associated with the transactivation of RARE-dependent transcription. These findings suggest a mechanism of anti-proliferative action of beta-cryptoxanthin and indicate that beta-cryptoxanthin may be a promising chemopreventive agent against lung cancer.