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The Impact of One-Week Dietary Supplementation with Kava On Published OnlineFirst February 26, 2020; DOI: 10.1158/1940-6207.CAPR-19-0501 CANCER PREVENTION RESEARCH | RESEARCH ARTICLE The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers Yi Wang1, Sreekanth C. Narayanapillai1, Katelyn M. Tessier2, Lori G. Strayer2, Pramod Upadhyaya2,QiHu1, Rick Kingston3, Ramzi G. Salloum4, Junxuan Lu5, Stephen S. Hecht2, Dorothy K. Hatsukami2,6, Naomi Fujioka2,7, and Chengguo Xing1 ABSTRACT ◥ Tobacco smoking is the primary risk factor for lung pyridyl)-1-butanol (NNAL plus its glucuronides, major cancer, driven by the addictive nature of nicotine and the metabolites of NNK) before and after kava administration indisputable carcinogenicity of 4-(methylnitrosamino)-1- as an indicator of NNK detoxification. Secondary objec- (3-pyridyl)-1-butanone (NNK) as well as other compounds. tives included determining kava's safety, its effects on The integration of lung cancer chemoprevention with smok- DNA damage, tobacco use, and cortisol (a biomarker of ing cessation is one potential approach to reduce this risk and stress). Kava increased urinary excretion of total NNAL mitigate lung cancer mortality. Experimental data from our and reduced urinary 3-methyladenine in participants, group suggest that kava, commonly consumed in the suggestive of its ability to reduce the carcinogenicity of South Pacific Islands as a beverage to promote relaxation, NNK. Kava also reduced urinary total nicotine equiva- mayreducelungcancerriskbyenhancingNNKdetoxi- lents, indicative of its potential to facilitate tobacco ces- fication and reducing NNK-derived DNA damage. Build- sation. Plasma cortisol and urinary total cortisol equiva- ing upon these observations, we conducted a pilot clinical lents were reduced upon kava use, which may contribute trial to evaluate the effects of a 7-day course of kava on to reductions in tobacco use. These results demonstrate NNK metabolism in active smokers. The primary objective the potential of kava intake to reduce lung cancer risk was to compare urinary total 4-(methylnitrosamino)-1-(3- among smokers. Introduction factor and tobacco cessation is the only strategy to date proven to mitigate lung cancer risk. The success rate of tobacco In spite of recent advances in immunotherapy, lung cancer cessation with currently available therapies, however, remains remains the leading cause of cancer-related deaths, with an low (2). Novel approaches, such as the integration of lung estimated 140,000 deaths and over 200,000 new cases annually cancer prevention in conjunction with tobacco cessation, are in the United States (1). Cigarette smoking is the major risk urgently needed. Tobacco smoke contains various carcinogens and co- carcinogens, collectively contributing to the increased lung 1Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 2 cancer risk. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Gainesville, Florida. Masonic Cancer Center, University of Minnesota, Minnea- fi polis, Minnesota. 3College of Pharmacy, University of Minnesota, Minneapolis, (NNK) is one of the best characterized tobacco-speci c lung Minnesota. 4Department of Health Outcome & Biomedical Informatics, College carcinogens, demonstrating potent pulmonary carcinogenicity of Medicine, University of Florida, Gainesville, Florida. 5Department of Pharma- in multiple species (3). Ample evidence support NNK as a key cology and Cancer Institute, Penn State, Hershey, Pennsylvania. 6Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota. 7Division of Hema- causative factor of human lung adenocarcinoma develop- tology, Oncology and Transplantation, Department of Medicine, University of ment (4–7). For instance, by analyzing the prospective samples Minnesota, Minneapolis, Minnesota. from the Prostate, Lung, Colorectal, and Ovarian Cancer Note: Supplementary data for this article are available at Cancer Prevention (PLCO) Screening Trial, Church and colleagues demonstrated Research Online (http://cancerprevres.aacrjournals.org/). that plasma 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol Corresponding Authors: Chengguo Xing, University of Florida, 1345 Center (NNAL, a major metabolite of NNK) was significantly asso- Drive, Gainesville, FL 32610. Phone: 352-294-8511; Fax: 352-273-9724; E-mail: ciated with increased lung cancer risk, even after correcting for fl [email protected] .edu; and Naomi Fujioka, [email protected] age and smoking duration (7). Polymorphisms of genes Cancer Prev Res 2020;13:483–92 involved in NNK metabolism (both bioactivation and detox- doi: 10.1158/1940-6207.CAPR-19-0501 ification) are also associated with differential lung cancer Ó2020 American Association for Cancer Research. risk (8). Prospective cohort studies found that urinary NNAL AACRJournals.org | 483 Downloaded from cancerpreventionresearch.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst February 26, 2020; DOI: 10.1158/1940-6207.CAPR-19-0501 Wang et al. was positively associated with lung cancer risk in smo- Deuterium-labeled dihydromethysticin (2H-DHM) was syn- kers (9, 10), after correcting for cigarettes smoked per day and thesized and characterized by both NMR and mass spectrom- 2 2 2 years of smoking, directly linking NNK exposure to lung cancer etry (30). [ H4]-nicotine, [ H3]-cotinine, and [ H3]-3-OH- 13 development. cotinine were purchased from Sigma-Aldrich. [ C6]-NNAL, 2 2 N 2 2 The mechanism of NNK carcinogenesis has been well char- [ H3]-3-mA, [ H3]-nicotine- -oxide, [ H4]-cortisol, [ H4]- b 2 a 2 acterized (Fig. 1). Activation of NNK generates two types of 6 -hydroxycortisol, [ H6]-allo-3 -tetrahydrocortisol, [ H8]- 2 reactive species, leading to DNA damage (3). NNK can be cortisone, and [ H6]-tetrahydrocortisone were purchased from reduced to NNAL, the major metabolite in human smo- Toronto Research Chemicals. Optima LC/MS grade H2O, fi kers (11). NNAL is glucuronidated, leading to its detoxi cation HCO2H, CH3OH, and CH3CN were purchased from Thermo via excretion as NNAL-Gluc (12), which would reduce the Fisher Scientific. Strata-X cartridges (33 mm, 30 mg/L) were carcinogenic risk of NNK (13). At the same time, NNAL can purchased from Phenomenex. Oasis MCX cartridges (30 mg) be bioactivated to generate two types of reactive species to were purchased from Waters. b-Glucuronidase and other form DNA damage. DNA damage is widely accepted as the chemicals were purchased from Sigma-Aldrich, unless stated root cause of NNK-induced carcinogenesis through mutagen- otherwise. esis (3). Some modified DNAs (DNA adducts), however, are not stable and are excreted in urine, which could serve as Profiling five major kavalactones noninvasive surrogates to estimate the level of DNA damage in Our method to quantify five major kavalactones (kavain, tissues. Among various urinary DNA adducts, we and others dihydrokavain, methysticin, DHM, and desmethoxyyangonin) demonstrated that human urinary 3-methyladenine (3-mA) in kava products was published elsewhere (30). Briefly, the dark appeared to be highly tobacco dependent (14–16) and may be brown viscous oil in three randomly selected capsules were indicative of NNK bioactivation (15). weighed and dissolved in a solution of DMSO:CH3OH (1:1) to Kava is traditionally consumed by the South Pacific Islanders 20 mg/mL. The solution was diluted to a final concentration of m 2 to promote natural calmness (17, 18). It is also marketed as a 20 pg/ L with 10% CH3OH in H2O. [ H2]-DHM was added as dietary supplement in the United States to help reduce stress. A the internal standard at a final concentration of 1.0 pg/mL. The group of kava-specific lactones (kavalactones, particularly samples (10 mL) were analyzed by ultraperformance liquid kavain and dihydrokavain; Supplementary Fig. S1) have been chromatography tandem mass spectrometry (UPLC/MS-MS). proposed to be responsible for this pharmacodynamic The amount of these five kavalactones was estimated to be effect (19, 20). Epidemiologic observations (21, 22) and pre- 77 mg/capsule (30). The same method was also used to quantify clinical animal studies (23–25) indicate that kava consumption DHM in the urine samples from the trial participants to assess may reduce cancer risk, particularly lung cancer (23, 26–28). kava exposure. We recently demonstrated that kava completely blocked NNK- induced lung tumorigenesis in A/J mice (23); dihydromethys- Clinical trial ticin (DHM; Supplementary Fig. S1) was identified as the active Twenty-one participants completed the clinical trial (Clin- ingredient with an efficacious dose in A/J mice (28) comparable icaltrials.gov NCT02500472), conducted at the University of to doses used in humans as dietary supplements (29). Mech- Minnesota. The study design is shown in Fig. 2. Eligible anistically, kava and DHM reduced NNK/NNAL-induced participants were adults (≥18 years of age) and current smokers DNA damage in A/J mouse lung tissues (23, 28), potentially (≥5 cigarettes per day by self-report). All participants had via enhancing NNAL urinary detoxification (26). normal blood counts, electrolytes, and liver function. Those Such mechanistic insight greatly improves the feasibility of with known hepatobiliary disease or impairment, conditions kava clinical evaluation because noninvasive NNK metabolites that might affect kava absorption such as gastric bypass or can serve as surrogates of kava's potential benefits. We herein celiac sprue, major or chronic medical disease,
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