Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing o6-methylguanine DNA adduct in A/J mice

Pablo Leitzman, Sreekanth C. Narayanapillai, Silvia Balbo, Bo Zhou, Pramod Upadhyaya, Ahmad Ali Shaik, M. Gerard O'Sullivan, Stephen S. Hecht, Junxuan Lu, Chengguo Xing

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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 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.

Original languageEnglish (US)
Pages (from-to)86-96
Number of pages11
JournalCancer Prevention Research
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2014

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Kava
DNA Adducts
Carcinogenesis
Lung
Adenoma
Diet
DNA Damage
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
O-(6)-methylguanine
Benzo(a)pyrene

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Leitzman, Pablo ; Narayanapillai, Sreekanth C. ; Balbo, Silvia ; Zhou, Bo ; Upadhyaya, Pramod ; Shaik, Ahmad Ali ; O'Sullivan, M. Gerard ; Hecht, Stephen S. ; Lu, Junxuan ; Xing, Chengguo. / Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing o6-methylguanine DNA adduct in A/J mice. In: Cancer Prevention Research. 2014 ; Vol. 7, No. 1. pp. 86-96.
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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 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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Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing o6-methylguanine DNA adduct in A/J mice. / Leitzman, Pablo; Narayanapillai, Sreekanth C.; Balbo, Silvia; Zhou, Bo; Upadhyaya, Pramod; Shaik, Ahmad Ali; O'Sullivan, M. Gerard; Hecht, Stephen S.; Lu, Junxuan; Xing, Chengguo.

In: Cancer Prevention Research, Vol. 7, No. 1, 01.01.2014, p. 86-96.

Research output: Contribution to journalArticle

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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

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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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