Quantifying NNK metabolites to facilitate Kava lung cancer prevention clinical translation

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ABSTRACT Lung cancer causes the most deaths among all cancers. Given the limited success in its early diagnosis and clinical treatment, risk reduction is essential in order to improve lung cancer management. Tobacco cessation should be the primary approach among smokers for lung cancer risk reduction. Current cessation interventions, however, are not very effective. Preventing tobacco-induced carcinogenesis could be complementary. Supported by human epidemiological data, pre-clinical animal data, a pilot trial, and equipped with mechanistic insights, kava is a promising candidate to reduce lung cancer risk among addicted smokers. Kava, which originates from the South Pacific Islands as a beverage, reduces stress and improves sleep. An inverse relationship between kava consumption and cancer incidence, particularly lung cancer, among the South Pacific Islanders suggests its potential in reducing cancer risks. We demonstrated that kava completely blocked lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (a tobacco specific lung carcinogen, commonly known as NNK) and other cancers in lab animals. One underlying mechanism is to enhance carcinogen detoxification and thus reduce carcinogen-induced DNA damage. Consistent with lab animal data, our pilot trial results showed that kava reduced lung cancer risk biomarkers among smokers. In order to improve kava’s translational feasibility and to maximize its lung cancer preventive benefits, this self-contained study aims to evaluate the potential of five mechanism-based non-invasive quantitative biomarkers in timely monitoring the efficacy of kava intervention and more importantly to explore the opportunities of kava precision prevention among smokers by analyzing these biomarkers and potential SNPs using banked pre-, during-, and post-kava urine, plasma and buffy coat samples from 21 smoker participants. Aim 1. To quantify three NNK-based urinary metabolites – free NNAL, NNAL-N-gluc and NNAL-O-gluc in the urine samples among 21 participants collected from the pilot trial before kava exposure (Day 0), during kava exposure (Day 4), and after kava exposure (Day 7). Specific UGT SNPs will be analyzed as well. Aim 2. To quantify two NNK-based plasma protein adducts – HPB and Diol in the plasma samples among 21 participants collected from the pilot trial before kava exposure (Day 0), during kava exposure (Day 4), and after kava exposure (Day 7).