Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing O6-methylguanine DNA adduct in A/J mice.
Kava blocks 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in association with reducing O6-methylguanine DNA adduct in A/J mice.
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DOI：
10.1158/1940-6207.capr-13-0301
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Xing C
中科院分区：
文献类型：
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作者：
Leitzman P;Narayanapillai SC;Balbo S;Zhou B;Upadhyaya P;Shaik AA;O'Sullivan MG;Hecht SS;Lu J;Xing C
我们先前报道了卡瓦对4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）和苯并（a）芘（BaP）诱导的A/J小鼠在起始和起始后阶段的肺肿瘤发生的化学预防潜力。在这项研究中，我们研究了卡瓦的肿瘤发生阶段特异性，潜在的活性化合物，以及NNK诱导的A/J小鼠肺肿瘤发生的潜在机制。在第一个实验中，在不同时期给予NNK处理的小鼠含有剂量为5 mg/g饮食的卡瓦的饮食。卡瓦治疗涵盖了初始阶段，减少了约99%的肺腺瘤的多样性。最小有效剂量尚未确定，因为两种较低剂量（2.5和1.25 mg/g饮食）的卡瓦在完全抑制肺腺瘤形成方面与5 mg/g饮食同样有效。每天管饲卡瓦（在NNK处理之前、期间和之后一次）也完全阻断肺腺瘤形成。富含卡法根内酯的级分B完全概括了卡瓦的化学预防功效，而不含卡法根内酯的级分A和C的有效性低得多。在机制上，卡瓦和级分B减少肺组织中NNK诱导的DNA损伤，其中独特且优先减少O 6-甲基鸟嘌呤（O 6-mG），NNK的高度致瘤性DNA损伤，与阻断肺腺瘤形成的功效相关并预测其功效。总之，这些结果证明了卡瓦在预防A/J小鼠中NNK诱导的肺肿瘤发生方面的突出功效，其对起始阶段具有高选择性，与DNA中O 6-mG加合物的减少相关。它们还为卡法根中活性化合物的鉴定奠定了知识基础。
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 post-initiation 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 ~ 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 complete 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 while 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.