kava and Lung-Neoplasms

Lung cancer is the leading cause of cancer-related deaths due to its high incidence, late diagnosis, and limited success in clinical treatment. Prevention therefore is critical to help improve lung cancer management. Although tobacco control and tobacco cessation are effective strategies for lung cancer prevention, the numbers of current and former smokers in the USA and globally are not expected to decrease significantly in the near future. Chemoprevention and interception are needed to help high-risk individuals reduce their lung cancer risk or delay lung cancer development. This article will review the epidemiological data, pre-clinical animal data, and limited clinical data that support the potential of kava in reducing human lung cancer risk via its holistic polypharmacological effects. To facilitate its future clinical translation, advanced knowledge is needed with respect to its mechanisms of action and the development of mechanism-based non-invasive biomarkers in addition to safety and efficacy in more clinically relevant animal models.

Topics: Animals; Biomarkers; Chemoprevention; Humans; Kava; Lung Neoplasms

Tobacco use is the leading cause of many preventable diseases, resulting in premature death or disease. Given that the majority of adult who smoke want to stop, this health burden could be significantly reduced if the success rate of tobacco cessation can be improved. In addition, most adults planning to quit were interested in trying complementary approaches to facilitating tobacco cessation, which is currently lacking. Therefore, there is an unmet and urgent need for novel interventions to improve the success of tobacco cessation. If such an intervention can reduce tobacco-associated lung carcinogenesis, that will be more desirable. The goal of this project is to develop a safe and effective kava-based intervention to enable tobacco cessation and reduce lung cancer risk, which will improve the health of smokers.. A randomized controlled trial will enroll 80 adults who currently smoke at least 10 cigarettes daily and randomize 1:1 into the placebo and AB-free kava arms, being exposed for 4 weeks, with a total of six visits (weeks 0, 1, 2, 4, 8, and 12) to evaluate the compliance and potential issues of AB-free kava use among the participants, explore the potential effect of the AB-free kava intervention on tobacco dependence, tobacco use, and lung carcinogenesis biomarkers. Participants will be enrolled during their primary care clinic visit.. Primary care settings play a critical role in tobacco-related disease screening, counseling, and early intervention, as the majority of adults who smoke visit their physicians annually. Building upon our promising pilot human trial results in conjunction with ample compelling lab animal results, and consistent with evidence of kava's benefits from epidemiological data, this trial will evaluate the compliance of AB-free kava among adults who currently smoke with no intention to quit. The other exploratory aims include (1) whether AB-free kava intervention can reduce tobacco use and tobacco dependence; (2) whether AB-free kava use suppresses tobacco-induced carcinogenesis; and (3) the potential of the mechanism-based noninvasive biomarkers in precision AB-free kava intervention. The positive results from this study are expected to provide a great opportunity to effectively reduce smoking rates and tobacco-related diseases.. ClinicalTrials.gov with the identifier: NCT05081882. Registered on October 18, 2021.

Topics: Adult; Biomarkers; Humans; Kava; Lung; Lung Neoplasms; Nicotiana; Randomized Controlled Trials as Topic; Smoking Cessation; Tobacco Use Disorder

Kava, the extract of the roots of

Topics: Anti-Anxiety Agents; Antineoplastic Agents, Phytogenic; Calcium; Cell Line, Tumor; Humans; Kava; Lactones; Lung Neoplasms; Norepinephrine; Plant Extracts; Stress, Psychological

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.

Topics: Adolescent; Adult; Biomarkers; Carcinogenesis; Carcinogens; Case-Control Studies; Dietary Supplements; DNA Damage; Female; Follow-Up Studies; Humans; Kava; Lung Neoplasms; Male; Middle Aged; Nitrosamines; Pilot Projects; Prognosis; Smokers; Tobacco Use; Young Adult

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.

Topics: Adenoma; Animal Feed; Animals; Anticarcinogenic Agents; Benzo(a)pyrene; Carcinogenesis; Carcinogens; DNA Adducts; DNA Damage; Female; Guanine; Kava; Lung; Lung Neoplasms; Mice; Nitrosamines

We have previously shown that kava and its flavokavain-free Fraction B completely blocked 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice with a preferential reduction in NNK-induced O (6)-methylguanine (O (6)-mG). In this study, we first identified natural (+)-dihydromethysticin (DHM) as a lead compound through evaluating the in vivo efficacy of five major compounds in Fraction B on reducing O (6)-mG in lung tissues. (+)-DHM demonstrated outstanding chemopreventive activity against NNK-induced lung tumorigenesis in A/J mice with 97% reduction of adenoma multiplicity at a dose of 0.05mg/g of diet (50 ppm). Synthetic (±)-DHM was equally effective as the natural (+)-DHM in these bioassays while a structurally similar analog, (+)-dihydrokavain (DHK), was completely inactive, revealing a sharp in vivo structure-activity relationship. Analyses of an expanded panel of NNK-induced DNA adducts revealed that DHM reduced a subset of DNA adducts in lung tissues derived from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the active metabolite of NNK). Preliminary 17-week safety studies of DHM in A/J mice at a dose of 0.5mg/g of diet (at least 10× its minimum effective dose) revealed no adverse effects, suggesting that DHM is likely free of kava's hepatotoxic risk. These results demonstrate the outstanding efficacy and promising safety margin of DHM in preventing NNK-induced lung tumorigenesis in A/J mice, with a unique mechanism of action and high target specificity.

Topics: Animals; Carcinogens; DNA Adducts; DNA Damage; Dose-Response Relationship, Drug; Female; Guanine; Kava; Liver; Lung Neoplasms; Mice; Mice, Inbred Strains; Nicotiana; Nitrosamines; Pyrones; Structure-Activity Relationship

We are interested in investigating the biological activity of chalcones, a major class of compounds found in the beverage kava, in order to develop potent and selective chemopreventive candidates. Consumption of kava in the South Pacific Islands is inversely correlated with cancer incidence, even among smokers. Accordingly, chalcones have anti-cancer activities in animal and cell culture models. To investigate signaling pathways that affect chalcone action we studied a potent analog, (E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (chalcone-24). Chalcone-24 was selected from a series of chalcone analogs that were synthesized based on the structures derived from flavokawain compounds found in kava, and screened in A549 lung cancer cells for induction of cytotoxicity and inhibition of NF-κB, a transcription factor associated with cell survival. Incubation of A549 cells with chalcone-24 resulted in a dose-dependent inhibition of cell viability, inhibition of NF-κB, activation of caspases, and activation of extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK); ERK1/2 and JNK are mitogen activated protein kinases that play central roles in regulating cell fate. Pharmacological inhibitors of ERK1/2 or JNK increased the sensitivity of A549 cells to chalcone-24-induced cytotoxicity, without affecting NF-κB or caspase activity. These results will help refine the synthesis of chalcone analogs to maximize the combination of actions required to prevent and treat cancer.

Topics: Cell Survival; Chalcone; Chalcones; Drug Resistance, Neoplasm; Humans; Kava; Lung Neoplasms; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Neoplasms

Lung cancer is the most deadly malignancy in the US. Chemoprevention is potentially a complementary approach to smoking cessation for lung cancer control. Recently, we reported that a commercially available form of kava extract significantly inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BaP)-induced lung tumorigenesis in A/J mice at a dose of 10 mg per gram diet. In the present study, we examined the dose-dependent lung tumor inhibitory activities of kava and investigated potential active constituent(s). Mice treated with carcinogen alone contained 12.1±5.8 lung adenomas per mouse 22 weeks after final carcinogen administration. Mice that were fed diets containing kava at dosages of 1.25, 2.5, 5, and 10 mg/g of diet had 8.4±3.5, 6.6±3.5, 4.3±2.4, and 3.8±2.3 lung adenomas per mouse, respectively. This corresponds to a reduction of 31%, 46%, 65% and 69% in tumor multiplicity, which were all statistically significant (p < 0.05). Analyses of lung adenoma tissues derived from kava-treated animals revealed that kava significantly inhibited adenoma cell proliferation while it had no detectable effect on cell death, indicating that kava primarily suppressed lung tumorigenesis in A/J mice via inhibition of cell proliferation. Flavokawains A, B, and C, three chalcone-based components from kava, demonstrated greatly reduced chemopreventive efficacies even at concentrations much higher than their natural abundance, suggesting that they alone were unlikely to be responsible for kava's chemopreventive activity. Kava at all dosages and treatment regimens did not induce detectable adverse effects, particularly with respect to liver. Specifically, kava treatment showed no effect on liver integrity indicator enzymes or liver weight, indicating that kava may be potentially safe for long-term chemopreventive application.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents, Phytogenic; Benzo(a)pyrene; Carcinogens; Cell Death; Cell Proliferation; Chalcone; Dose-Response Relationship, Drug; Female; Kava; Liver; Lung Neoplasms; Mice; Mice, Inbred Strains; Nitrosamines; Phytotherapy; Plant Extracts

Lung cancer is the leading cause of cancer death, and chemoprevention is a potential strategy to help control this disease. Epidemiologic survey indicates that kava may be chemopreventive for lung cancer, but there is a concern about its potential hepatotoxicity. In this study, we evaluated whether oral kava could prevent 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (B[a]P)-induced lung tumorigenesis in A/J mice. We also studied the effect of kava to liver. At a dose of 10 mg/g diet, 30-week kava treatment (8 weeks concurrent with NNK and B[a]P treatment followed by 22 weeks post-carcinogen treatment) effectively reduced lung tumor multiplicity by 56%. Kava also reduced lung tumor multiplicity by 47% when administered concurrently with NNK and B[a]P for 8 weeks. Perhaps most importantly, kava reduced lung tumor multiplicity by 49% when administered after the final NNK and B[a]P treatment. These results show for the first time the chemopreventive potential of kava against lung tumorigenesis. Mechanistically, kava inhibited proliferation and enhanced apoptosis in lung tumors, as shown by a reduction in proliferating cell nuclear antigen (PCNA), an increase in caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Kava treatment also inhibited the activation of nuclear factor kappaBNF-kappaB, a potential upstream mechanism of kava chemoprevention. Although not rigorously evaluated in this study, our preliminary data were not suggestive of hepatotoxicity. Based on these results, further studies are warranted to explore the chemopreventive potential and safety of kava.

Topics: Adenoma; Algorithms; Animals; Antineoplastic Agents; Apoptosis; Benzo(a)pyrene; Body Weight; Cell Proliferation; Chemoprevention; Drug Evaluation, Preclinical; Eating; Female; Kava; Lung Neoplasms; Mice; Neoplasms, Multiple Primary; Nitrosamines; Plant Extracts