Title of Research: Kava, dihydromethysticin and NNK-induced lung cancer: from lab animals to humans
Additional Authors: P. Corral; S. Narayanapillai; P. Leitzman; P. Upadhyaya; M. O’Sullivan; SS. Hecht; J. Lu; C. Xing
Lung cancer is the leading cause of cancer deaths worldwide, with limited success in early diagnosis or treatment. Tobacco exposure is the dominant risk factor because it contains a range of carcinogens and co-carcinogens. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (commonly known as NNK) is the most potent tobacco-specific carcinogen that effectively induces lung tumor formation in various species. Kava is a beverage consumed by the South Pacific Islanders to help relax and sleep. Supported by human epidemiological data, we have demonstrated its lung cancer chemopreventive efficacy and identified dihydromethysticin (DHM) as the active compound using the NNK-induced lung tumorigenesis A/J mouse model.
In this presentation, we will discuss our recent data supporting its human translation. First, we performed additional lab animal studies to validate the efficacy, optimize the dosing schedule, and further elucidate the mechanisms using oral bolus dosing of DHM. Our results suggest that DHM treatment reduced the formation of NNK-induced O6-methylguanine (O6-mG, a carcinogenic DNA adduct in A/J mice) in the target lung tissue and increased the urinary excretion of NNK detoxification metabolites as indicated by the ratio of urinary NNAL-O-Gluc to free NNAL, generally in synchrony with the tumor prevention efficacy outcome. We then conducted a pilot clinical trial to evaluate the effects of a 7-day kava exposure on NNK metabolism in active smokers. Urinary NNAL-N-Gluc and NNAL-O-Gluc, the detoxification metabolites of NNK, and free NNAL were quantified. The results showed that kava treatment enhanced NNAL detoxification, particularly N-glucuronidation. Detailed mechanistic studies are ongoing to explore the potential of precision prevention.
About the author
I am Qi Hu from Department of Medicinal Chemistry. I was selected to participate in this year’s Oral Competition at the 34th Annual Research Showcase. I have attached my headshot here, and below is my short bio: Qi Hu is a 4th year graduate student in Department of Medicinal Chemistry. Currently she is working in Dr. Chengguo Xing’s lab. Her research focuses on carcinogenesis and chemoprevention of tobacco-induced lung cancer.