Highlights from a cross-sectional report, published in the International Journal of Molecular Sciences in 2023, entitled Opportunities and Challenges of Kava in Lung Cancer Prevention. Why Kava Kava could mean a breakthrough.
Opportunities and Challenges of Kava in Lung Cancer Prevention
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. […]
Lung cancer is the second most commonly diagnosed non-dermatological malignancy among both men and women globally, following prostate cancer and breast cancer, respectively [1,2]. At the same time, lung cancer has been the leading cause of cancer deaths for decades due to its relatively late diagnosis, poor treatment outcome, and high prevalence. There were about 2.2 million new lung cancer cases with 1.8 million deaths worldwide in 2020, representing approximately 11.4% of all cancers diagnosed and 18.0% of cancer caused deaths . […]
Kava against lung cancer: Potential, Mechanisms, and Challenges in Cancer Risk Reduction
Knowledge about Kava, Its Traditional Use and Potential Benefits
Traditionally, kava is a beverage prepared from the root of Piper methysticum, which belongs to the pepper family, that originated and is dominantly cultivated in the South Pacific islands. Kava has been consumed by indigenous peoples for centuries as a religious and celebratory drink . Kava gradually evolved into a common beverage among the South Pacific Islanders due to its relaxing properties [82,83,84,85]. The active components in kava for relaxation include lactone-based compounds termed kavalactones  with kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin as the six major ones (Figure 2).
Despite their high structural similarity, these natural kavalactones have distinct pharmacokinetic  and pharmacodynamic properties [88,89]. It is therefore possible that these kavalactones may be complementary to each other and none of them individually will be able to fully recapitulate the holistic beneficial properties of kava. Other than kavalactones, a class of chalcone based compounds have been detected in kava products and heavily investigated, named flavokavains A, B, and C (Figure 2) . These flavokavains have not been reported to contribute to kava’s relaxing property. A number of putative targets have been reported for kavalactones, including voltage-gated sodium and calcium ion channels, gamma-aminobutyric acid (GABA) type A receptors, and monoamine oxidase B (MAO-B), with detailed information in our previous review .
Historically, the types of kava products (chemotype) have been characterized by their relative abundance of individual kavalactones . Kava products of different chemotypes have been proposed to possess varied benefits and risks, because of different composition profiles of kavalactones and flavokavains . Other than in the format of a drink, kava has also been commercialized in the form of capsules or tinctures as dietary supplements. Because of these variables, currently available kava products could be very diverse due to their difference in format, kavalactone abundance and profiles, and the content of other ingredients, such as flavokavains A and B [94,95,96]. Not surprisingly, various benefits and risks could potentially be introduced due to these chemical composition variations. Commercial kava products thus should be rigorously standardized with accurate content information for human use, particularly in the case of potential chronic use, such as its potential use in primary lung carcinogenesis prevention .
Epidemiological Data Supporting Kava in Cancer Risk Reduction
In the year 2000, Steiner first proposed the potential of kava to reduce human cancer risk . Briefly, an inverse relationship between kava consumption and cancer incidence among several islands in the South Pacific was reported by Steiner, leading to the hypothesis that kava may have the potential to reduce cancer risk.
In addition, cancer incidence rates were lower in males relative to females in South Pacific nations with higher kava consumption, which is the opposite of global trends, as previously mentioned . Given that traditional kava is dominantly consumed by males, the lower cancer incidence among males versus females in nations with high kava consumption also supports kava’s potential to prevent cancer. In this report, cancer incidence includes all types of cancers. It is possible that kava may have differential effects among different cancer types, which has not yet been rigorously investigated. A limited number of potential confounding variables other than kava were briefly analyzed as well, such as smoking rate, which was found to be comparable among those nations and may not contribute to the observed cancer incidence differences . Several other epidemiological data also indicate lower cancer incidence among males in comparison to females in the South Pacific [99,100], which is again opposite to the global trend , further substantiating kava’s potential in reducing human cancer risk. […]
Kava against Lung Cancer: Potential in Cancer Risk Reduction in Animal Models, Responsible Ingredients, and Mechanisms
Stimulated by these interesting human epidemiological data, kava’s potential to reduce cancer risk has been evaluated during the past two decades using various chemical-induced or transgenic animal models, including lung, prostate, colon, and bladder tumorigenesis [53 ,54, 89, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111]. In these animal models, tumorigenesis was induced by genetic mutations or different chemical carcinogens via different administration routes. Kava, via gavage or in the form of diet, has also been administered via different regimens, either during or after carcinogen exposure in the chemical carcinogenesis model. […]
The positive results of kava to prevent tumorigenesis in all of these animal models strongly suggest that kava may reduce human cancer risk, likely via different mechanisms.
In fact, different kavalactones have been identified as the active ingredients in some of these carcinogenesis models. For instance, dihydromethysticin has been identified as one active compound that can effectively suppress NNK-induced lung carcinogenesis in A/J mice  while kavain was recently identified to prevent bladder carcinogenesis induced by hydroxy butyl(butyl) nitrosamine (OH-BBN) in mice . Although kavain has not been evaluated for its potential against NNK-induced lung carcinogenesis, it is less likely to be as effective as dihydromethysticin in this model based on its lack of efficacy in reducing NNK-induced DNA damage in target lung tissue . These results also argue that maybe none of the single-chemical entities in kava are capable of fully recapitulating the holistic benefits of kava in cancer risk reduction, upon which the human epidemiological data are built. This is particularly important for human translation. Kava, a natural blend of kavalactones with historical human exposure and epidemiological support, may be the ideal candidate instead of any single chemical from kava as long as the kava product has rigorous quality control and quality assurance.
With respect to its potential in preventing lung carcinogenesis, kava was first evaluated against lung carcinogenesis induced by eight oral dosages of NNK and BaP in A/J mice . Kava was supplemented in the diet with three different treatment regimens, covering only the carcinogen exposure period (mimicking current smokers), covering the postcarcinogen exposure period (mimicking former smokers), and covering the whole experimental period. […]
Preliminary mechanistic investigation suggests that kava inhibited the activation of nuclear factor kappa B (NF-κB) . Given that chronic lung inflammation is a well-established risk factor for lung cancer, kava may prevent lung carcinogenesis in this animal model at least in part by suppressing tobacco-induced lung inflammation. Chalcone-based flavokavains (Figure 2) in kava were initially hypothesized as the responsible active ingredients since many chalcone-based compounds have been reported with cancer preventive potential in various animal models . Our data later rejected this hypothesis as flavokavains from kava, at several dosages, failed to capture the preventive efficacy of kava in this animal model . Additional medicinal chemistry efforts from our lab were able to develop analogs of the flavokavains with a wide range of bioactivity in cell models, but none of them were able to block lung carcinogenesis in this animal model and some compounds showed significant toxicity (unpublished data). The traditional approach for active ingredient identification, fractionation and biological evaluation, was adopted to search for the active chemicals . The fraction enriched with kavalactones was able to recapitulate the preventive efficacy of kava in a two-dose NNK-induced lung carcinogenesis A/J mouse model and dihydromethysticin was identified as an active compound . Dihydrokavain was demonstrated completely inactive in this animal model, which later was used as a control compound for mechanistic elucidation. Based on their distinct effects in reducing NNK-induced DNA damage, methysticin is likely active as well while kavain would not in this animal model .
Extensive structure–activity relationship studies have been performed on dihydromethysticin to characterize the functional groups important for its lung cancer preventive activity [101,102,108] but to date none of the synthetic compounds were able to outperform the natural dihydromethysticin except the unnatural enantiomer of dihydromethysticin. It should be noted that the dose range of kava and natural dihydromethysticin, with effective lung cancer prevention in these animal studies, was comparable to the levels of traditional kava consumption in humans. […]
Thus, in alignment with the epidemiologic data, kava may be potent enough to reduce human lung cancer risk in its natural format. […]
At the same time, chronic lung inflammation is a well-established risk factor for lung carcinogenesis. Several kavalactones have demonstrated anti-inflammatory activities in vivo [85,113,114,115,116,117,118,119,120,121,122]. For instance, kavain inhibits lipopolysaccharide (LPS)-induced collagen antibody induced arthritis in mice . Desmethoxyyangonin inhibits LPS-induced inflammation and LPS/D-galactosamine-induced hepatitis in mice . […]
Therefore, kava may be able to reduce lung cancer risk partly through its anti-inflammatory activities. However, the two-dose NNK-induced lung tumorigenesis animal model, as discussed above, does not appear to recapitulate the chronic inflammatory nature of lung cancer risk in humans. Future work is needed to characterize the anti-inflammatory contribution of kava to reduce lung cancer risk via clinically more relevant animal models. Kava may also reduce lung cancer risk through its relaxing property if chronic mental stress is a valid risk for lung cancer. Thus, the potential contribution of stress reduction to kava’s lung cancer risk also requires future investigation. Indeed, kava revealed the potential to reduce tobacco use and tobacco dependence among smokers in a pilot clinical trial , which may be mediated through its relaxing properties as reflected by the reduction in the plasma levels of cortisol . […]
In summary, kava may reduce lung cancer risk via multiple mechanisms, namely reducing tobacco use and dependence, enhancing tobacco carcinogen detoxification and thus reducing DNA damage, suppressing tobacco smoke-induced lung inflammation, and promoting relaxation. […]
Although the focus of this review is kava’s potential in primary lung cancer prevention, compounds in kava, primarily flavokavains, have also been reported to reveal anticancer potentials. Specifically, flavokavains A and B have been reported to exhibit anticancer activity in multiple cancer cell models including lung, breast , bladder , and prostate . They were able to inhibit cancer cell proliferation , angiogenesis , metastasis , or modulate immune responses [146,147]. […]
As discussed, lung cancer is induced by multiple risk factors. Thus, a single-chemical entity is less likely to achieve effective lung cancer prevention, due to the low probability of it exhibiting polypharmacological effects against different risk factors. Indeed, this is well demonstrated in the past lung cancer preventive endeavors between individual chemicals vs. natural mixtures, such as green tea vs. EGCG and vegetable juice vs. PEITC or indole-3-carbinol. Specifically, EGCG, PEITC, and indole-3-carbinol were identified as the active ingredients from green tea and vegetables via cell-based or simplified animal models, but all of them failed to fully recapitulate the efficacy of their corresponding natural mixture entities in later translation. Similarly, our data and the numerous literature reports suggest that despite the structural similarities of the different compounds present in kava, such as kavalactones, they each have distinct beneficial activities. They may act complementarily to each other to achieve the polypharmacological goal for effective lung cancer risk reduction, such as carcinogen detoxification, inflammation inhibition, and stress reduction in addition to their distinct pharmacokinetic properties.
Furthermore, kava’s potential to reduce cancer risk is based on kava’s traditional use by humans in the form of its natural mixture rather than any single-chemical entities (Table 2). Lastly and potentially most importantly, the historical long-term human consumption data provide a key safety foundation for the translation of natural blend kava, which is currently lacking for any of its single-chemical entities.
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