Carcinogenesis Advance Access originally published online on April 9, 2007
Carcinogenesis 2007 28(7):1567-1574; 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
Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA
1 BASF, Inc, Ludwigshafen D-67056, Germany
* To whom correspondence should be addressed. Tel: +1 617 556 3130; Fax: +1 617 556 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. (2006). J. Biol. Chem., 281, 19327–19338] 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 per mouse in the NNK injection alone group, to an average of 10, 7 and 5 tumors per 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.
Abbreviations: BEGM, bronchial epithelial growth medium; FBS, fetal bovine serum; i.p., intra-peritoneal; LDH, lactate dehydrogenase; NNK, 4-(N-methyl-N-nitrosamino)-1-(3-pyridal)-1-butanone; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PCR, polymerase chain reaction; RAR, retinoic acid receptor; RARE, retinoic acid response element; RLU, relative light unit; RXR, retinoid X receptor; SEM, standard error of mean; THF, tetrahydrofuran
Received December 1, 2006; revised February 23, 2007; accepted March 28, 2007.
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