title: Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing O6-methylguanine DNA adduct in A/J mice.
abstract: 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 O(6)-methylguanine (O(6)-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 O(6)-mG adduct in DNA. They also establish the knowledge basis for the identification of the active compound(s) in kava.
authors.affiliation: University of Minnesota, Department of Medicinal Chemistry, College of Pharmacy, 8-101 WDH, 308 Harvard Street SE, Minneapolis, MN 55455. xingx009@umn.edu.
authors.forename: Pablo
authors.initials: P
authors.lastname: Leitzman
authors.forename: Sreekanth C
authors.initials: SC
authors.lastname: Narayanapillai
authors.forename: Silvia
authors.initials: S
authors.lastname: Balbo
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.forename: Pramod
authors.initials: P
authors.lastname: Upadhyaya
authors.forename: Ahmad Ali
authors.initials: AA
authors.lastname: Shaik
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Hecht
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lu
authors.forename: Chengguo
authors.initials: C
authors.lastname: Xing
mesh_terms: D000236:Adenoma / Q000139:chemically induced / Q000517:prevention & control*; D000821:Animal Feed; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000737:chemistry; D063646:Carcinogenesis / Q000187:drug effects; D002273:Carcinogens; D018736:DNA Adducts / Q000737:chemistry*; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D020901:Kava / Q000737:chemistry*; D008168:Lung / Q000187:drug effects; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D009602:Nitrosamines / Q000737:chemistry
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D018736:DNA Adducts; D009602:Nitrosamines; D001564:Benzo(a)pyrene; D006147:Guanine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C008449:O-(6)-methylguanine