Dietary 5-demethylnobiletin inhibits cigarette carcinogen NNK-induced lung tumorigenesis in mice.
5-Demethylnobiletin (5DN) is a unique citrus flavonoid with various beneficial bioactivities. In this study, we determined the inhibitory effects of 5DN and its two major metabolites in the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis mouse model as well as in human and mouse lung cancer cell models. In NNK-treated female A/J mice, dietary administration of 5DN (0.025% or 0.05% w/w in the diet) significantly decreased both lung tumor multiplicity and tumor volume. Immunohistochemical analysis showed strong anti-proliferative effects of 5DN in lung tumors. Two major metabolites of 5DN, named 5,3'-didemethylnobiletin (M1) and 5,4'-didemethylnobiletin (M2), were found in the lung tissue of 5DN-fed mice. Cell culture studies demonstrated that 5DN, M1 and M2 significantly inhibited the growth of human and mouse lung cancer cells by causing cell cycle arrest, inducing apoptosis and modulating key signaling proteins related to cell proliferation and cell death. Interestingly, the metabolites of 5DN, especially M1 produced much stronger inhibitory effects on both human and mouse lung cancer cells than those produced by 5DN itself. Our results demonstrated that dietary administration of 5DN significantly inhibited NNK-induced tumorigenesis in mice, and this effect may be partially associated with the metabolites of 5DN in lung tissues.
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Mingyue
M
Song
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Xian
X
Wu
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Noppawat
N
Charoensinphon
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Minqi
M
Wang
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu and Institute of Agro-Products Processing Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, P.R. China.
Jinkai
J
Zheng
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Zili
Z
Gao
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Fei
F
Xu
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Zhengze
Z
Li
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Fang
F
Li
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Jiazhi
J
Zhou
Department of Food Science, University of Massachusetts, Amherst, MA, USA. hangxiao@foodsci.umass.edu.
Hang
http://orcid.org/0000-0002-6107-3532
H
Xiao
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000378:metabolism; D017209:Apoptosis; D063646:Carcinogenesis; D002273:Carcinogens / Q000633:toxicity*; D002957:Citrus / Q000737:chemistry*; D005260:Female; D047309:Flavones / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D009602:Nitrosamines / Q000633:toxicity*; D062789:Tobacco Products / Q000633:toxicity*
C000604601:5-demethylnobiletin; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D047309:Flavones; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone