Carcinogenesis Advance Access published online on April 9, 2007
Carcinogenesis, doi:10.1093/carcin/bgm076
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Apo-10'-lycopenoic acid inhibits lung cancer cell growth in vitro, and suppresses lung tumorigenesis in the A/J mouse model in vivo
1 Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111
2 BASF, Inc, Ludwigshafen, Germany
Requests for reprints: Xiang-Dong Wang, 711 Washington Street, Boston, MA 02111, USA. Telephone: 617-556-3130, Fax: 617-556-3344, Email: xiang-dong.wang{at}tufts.edu
High intake of lycopene has been associated with a lower risk of a variety of cancers including lung cancer. We recently showed that lycopene can be converted to apo-10'-lycopenoids (Hu et al., J. Biol. Chem. 281: 19327-38, 2006) in mammalian tissues both in vitro and in vivo, raising the question of whether apo-10'-lycopenoids have biological activities against lung carcinogenesis. In the present study, we report that apo-10'-lycopenoic acid inhibited the growth of NHBE normal human bronchial epithelial cells, BEAS-2B immortalized normal bronchial epithelial cells, and A549 non-small cell lung cancer cells. This inhibitory effect of apo-10'-lycopenoic acid was associated with decreased cyclin E, inhibition of cell cycle progression from G1 to S phase, and increased cell cycle regulators p21 and p27 protein levels. In addition, apo-10'-lycopenoic acid transactivated the retinoic acid receptor ß (RARß) promoter and induced the expression of RARß. We further examined the effect of apo-10'-lycopenoic acid treatment on 4-(N-methyl-N-nitrosamino)-1-(3-pyridal) -1-butanone (NNK)-induced lung tumorigenesis in the A/J mouse model. We found that the lung tumor multiplicity was decreased dose-dependently from an average of 16 tumors/mouse in the NNK injection alone group, to an average of 10, 7, and 5 tumors/mouse in groups injected with NNK and supplemented with 10, 40, and 120 mg/kg diet of apo-10'-lycopenoic acid, respectively. These observations demonstrate that apo-10'-lycopenoic acid is a biological active metabolite of lycopene and suggest that apo-10'-lycopenoic acid is a potential chemopreventive agent against lung tumorigenesis.
Key Words: Lycopene • apo-10'-lycopenoic acid • A/J mouse • lung cancer • RARß
Received December 1, 2006; revised February 23, 2007; accepted March 28, 2007.
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