University of Minnesota, Department of Medicinal Chemistry, College of Pharmacy, 8-101 WDH, 308 Harvard Street SE, Minneapolis, MN 55455.
Cancer Prev Res (Phila). 2014 Jan;7(1):86-96. doi: 10.1158/1940-6207.CAPR-13-0301.
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.
我们之前曾报道过，在 A/J 小鼠的起始和后续阶段，卡瓦提取物可预防 4-(甲基亚硝氨基)-1-(3-吡啶基)-1-丁酮（NNK）和苯并（a）芘（BaP）诱导的肺癌发生。在这项研究中，我们研究了卡瓦在 NNK 诱导的 A/J 小鼠肺癌发生中的肿瘤发生阶段特异性、潜在的活性化合物及其作用机制。在第一个实验中，NNK 处理的小鼠在不同时期给予含卡瓦 5mg/g 饮食的饮食。卡瓦治疗涵盖起始阶段，可使肺腺瘤的多发性降低约 99%。因为在两个较低剂量（2.5 和 1.25mg/g 饮食）下，卡瓦的效果与 5mg/g 饮食一样有效，所以还没有确定最小有效剂量，可完全抑制肺腺瘤形成。每日灌胃卡瓦（在 NNK 处理之前、期间和之后）也完全阻止了肺腺瘤的形成。卡瓦内酯富集的 B 部分完全再现了卡瓦的化学预防功效，而无卡瓦内酯的 A 和 C 部分则效果差得多。从机制上讲，卡瓦和 B 部分减少了 NNK 诱导的肺组织中的 DNA 损伤，具有独特的和优先的 O(6)-甲基鸟嘌呤（O(6)-mG）降低作用，O(6)-mG 是 NNK 引起的高度致癌性 DNA 损伤，与阻止肺腺瘤形成的疗效相关和具有预测性。总之，这些结果表明卡瓦在预防 A/J 小鼠 NNK 诱导的肺癌发生方面具有出色的功效，对起始阶段具有高度选择性，并与 DNA 中 O(6)-mG 加合物的减少相关。它们还为鉴定卡瓦中的活性化合物奠定了知识基础。
