TY - JOUR
T1 - Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing o6-methylguanine DNA adduct in A/J mice
AU - Leitzman, Pablo
AU - Narayanapillai, Sreekanth C.
AU - Balbo, Silvia
AU - Zhou, Bo
AU - Upadhyaya, Pramod
AU - Shaik, Ahmad Ali
AU - O'Sullivan, M. Gerard
AU - Hecht, Stephen S.
AU - Lu, Junxuan
AU - Xing, Chengguo
PY - 2014/1
Y1 - 2014/1
N2 - We previously reported the chemopreventive potential of kava against 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK)- and benzo(a)pyrene (BaP)-induced lung tumorigenesis in A/J mice during the initiation and postinitiation stages. In this study, we investigated the tumorigenesis-stage specificity of kava, the potential active compounds, and the underlying mechanisms in NNK-induced lung tumorigenesis in A/J mice. In the first experiment, NNK-treated mice were given diets containing kava at a dose of 5 mg/g of diet during different periods. Kava treatments covering the initiation stage reduced the multiplicity of lung adenomas by approximately 99%. A minimum effective dose is yet to be defined because kava at two lower dosages (2.5 and 1.25 mg/g of diet) were equally effective as 5 mg/g of diet in completely inhibiting lung adenoma formation. Daily gavage of kava (one before, during, and after NNK treatment) completely blocked lung adenoma formation as well. Kavalactone-enriched fraction B fully recapitulated kava's chemopreventive efficacy, whereas kavalactone-free fractions A and C were much less effective. Mechanistically, kava and fraction B reduced NNK-induced DNA damage in lung tissues with a unique and preferential reduction in O6-methylguanine (O6-mG), the highly tumorigenic DNA damage by NNK, correlating and predictive of efficacy on blocking lung adenoma formation. Taken together, these results demonstrate the outstanding efficacy of kava in preventing NNK-induced lung tumorigenesis in A/J mice with high selectivity for the initiation stage in association with the reduction of O6-mG adduct in DNA. They also establish the knowledge basis for the identification of the active compound(s) in kava.
AB - We previously reported the chemopreventive potential of kava against 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK)- and benzo(a)pyrene (BaP)-induced lung tumorigenesis in A/J mice during the initiation and postinitiation stages. In this study, we investigated the tumorigenesis-stage specificity of kava, the potential active compounds, and the underlying mechanisms in NNK-induced lung tumorigenesis in A/J mice. In the first experiment, NNK-treated mice were given diets containing kava at a dose of 5 mg/g of diet during different periods. Kava treatments covering the initiation stage reduced the multiplicity of lung adenomas by approximately 99%. A minimum effective dose is yet to be defined because kava at two lower dosages (2.5 and 1.25 mg/g of diet) were equally effective as 5 mg/g of diet in completely inhibiting lung adenoma formation. Daily gavage of kava (one before, during, and after NNK treatment) completely blocked lung adenoma formation as well. Kavalactone-enriched fraction B fully recapitulated kava's chemopreventive efficacy, whereas kavalactone-free fractions A and C were much less effective. Mechanistically, kava and fraction B reduced NNK-induced DNA damage in lung tissues with a unique and preferential reduction in O6-methylguanine (O6-mG), the highly tumorigenic DNA damage by NNK, correlating and predictive of efficacy on blocking lung adenoma formation. Taken together, these results demonstrate the outstanding efficacy of kava in preventing NNK-induced lung tumorigenesis in A/J mice with high selectivity for the initiation stage in association with the reduction of O6-mG adduct in DNA. They also establish the knowledge basis for the identification of the active compound(s) in kava.
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U2 - 10.1158/1940-6207.CAPR-13-0301
DO - 10.1158/1940-6207.CAPR-13-0301
M3 - Article
C2 - 24403291
AN - SCOPUS:84892385065
SN - 1940-6207
VL - 7
SP - 86
EP - 96
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 1
ER -