Kava Research The Correlation between Cancer Incidence and Kava Consumption

[verticity]

I happened across this paper that points out a the low incidence of cancer in countries where kava is consumed (pdf attached). There are a lot of problems with the paper (the apples-to-oranges comparison of reported incidence of disease in developed vs. developing countries; the uncertainty of trying to assign causality to one particular aspect of a culture to a specific statistic, etc.). It's not a rigorous paper at all, but it is interesting to consider this in light of recent finding laboratory findings that kava (and flavokavains in particular) may have a protective effect against cancer.
http://www.sciencedirect.com/science/article/pii/S0944711316302045
But the level of rigor is comparable to the studies showing elevated GGT enzymes in small cohorts, so I'm throwing it out there for discussion. Any speculation about the effect kava consumption might have on overall population mortality levels (and there is no evidence that it has any effect, either pro or con), needs to consider this.

Note the above in vitro study has statistics for the specific case of colon cancer in the Pacific Islands, but also notes that they are low. Quote:

"There is a low incidence of colon cancer in the South Pacific Islands, including Fiji, West Samoa, and Vanuatu (Steiner, 2000; Foliaki. et al., 2011). The incidence of cancer (2000–2005) is lower for people in the Pacific (Tonga, Fiji, Cook Islands, Niue) compared to Pacific people living in New Zealand (Age-standardized cancer incidence rates: 315 per 100,00 person-years in females, 379 in males), which is similar to the rates for New Zealand overall. For Fiji, the rates were 231 and 126 (per 100,00 person-years for females and males), respectively."

It is especially interesting to note the gender difference in cancer incidence, since in traditional kava drinking societies (and Fiji might be the best example today where the traditional culture still exists to a large extent) kava is only drunk by men.

 

[verticity]

Here's a pdf of the in vitro study.

 

[verticity]

Several articles on flavokavains killing cancer cells (actually quite a large number of recent articles about this!)

Flavokawain A, a Novel Chalcone from Kava Extract, Induces Apoptosis in Bladder Cancer Cells

Flavokawain B, a kava chalcone, induces apoptosis via up-regulation of death-receptor 5 and Bim expression in androgen receptor negative, hormonal refractory prostate cancer cell lines and reduces tumor growth

Flavokawain B induces apoptosis of non-small cell lung cancer H460 cells via Bax-initiated mitochondrial and JNK pathway

The flavokawains: uprising medicinal chalcones

In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice

 

[PepperyPyrone]

@verticity sorry, I have been meaning to get to this post and on your other kavascience forum. My apologies. I have found it interesting the specific influences of Flavokawain A and B on cancer cells, but don't they cause apoptosis on normal hepatocytes in vitro? I think there is a link with noble kava and anti-cancer effects, especially with papers like the Steiner paper speak volumes over in vitro assays with cell lines. It seems like these days, I am constantly seeing reports of some herb that kills cancer cells in vitro. So I am immune to new reports of something else that kills cancer cells. Now if they isolate the compound that is responsible and find the mechanism of action behind it, now that is good stuff. Do you know if any pharma companies have jumped on the flavokawains as maybe targeted tumor injectables? I read a cool article about maybe Fijians and decreased lung cancer incidence due to an kava-modulated CYP1A2 hydrocarbon metabolite and decreased phenacetin maybe? Have you run across this article, I can't seem to find it again.

 

[PepperyPyrone]

Based on the Einbond paper, I think I need to get me some Sea Hibiscus to strain with !

 

[verticity]

@verticity sorry, I have been meaning to get to this post and on your other kavascience forum. My apologies. I have found it interesting the specific influences of Flavokawain A and B on cancer cells, but don't they cause apoptosis on normal hepatocytes in vitro? I think there is a link with noble kava and anti-cancer effects, especially with papers like the Steiner paper speak volumes over in vitro assays with cell lines. It seems like these days, I am constantly seeing reports of some herb that kills cancer cells in vitro. So I am immune to new reports of something else that kills cancer cells. Now if they isolate the compound that is responsible and find the mechanism of action behind it, now that is good stuff. Do you know if any pharma companies have jumped on the flavokawains as maybe targeted tumor injectables? I read a cool article about maybe Fijians and decreased lung cancer incidence due to an kava-modulated CYP1A2 hydrocarbon metabolite and decreased phenacetin maybe? Have you run across this article, I can't seem to find it again.

Sure, I don't know. It could be that FKB is just toxic in general, in vitro, so it can kill both cancer cells but also healthy liver cells. And you are right that this kind of study is a far cry from something that could really be used therapeutically.

The suggestion that there could be something other than FKs in kava is interesting, and would make sense based on the epidemiological findings in Fiji and Samoa, places where pretty much only noble kava is grown and consumed.

On the other forum we were talking about this article about DHM:
https://www.ncbi.nlm.nih.gov/pubmed/27728767

Xing also wrote this saying probably methysticin has some effect:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756981/

This one is really interesting because it has a lot to say about the relative hepatotoxicity of various components, and also says that the FKs can't fully account for the chemoprotective effect:
"Commercial kava was first fractionated into four fractions by using silica gel chromatography (procedures in Supporting Information). These four fractions were analyzed for their compositions by HPLC following the same HPLC conditions. Fractions I and II mainly contain constituents present in both traditional and commercial kava while fractions III and IV only contain those constituents not detectable in traditional kava (Figure 1), including flavokawains A, B, and C in Fraction IV, which have been postulated to be the chemopreventive constituents in kava,27,28 while our in vivo chemopreventive evaluation indicates that these flavokawains cannot account for the significant chemopreventive activity of kava (manuscript in preparation for Cancer Prevention Research)."

Regarding in vitro toxicity to liver cells:
"Next we evaluated the relative toxicity of these chemicals against a liver cell line... Traditional kava and Fraction I of commercial kava demonstrated no toxicity ... Fractions II also demonstrated minimum toxicity to liver cells... Fraction III demonstrates a bit stronger toxicity ... Commercial kava... and Fraction IV... demonstrate significantly higher toxicity... ... Since Fraction IV is only detectable in commercial kava and both of them demonstrate high toxicity towards liver cells, the hepatotoxicity associated exclusively with commercial kava users may derive from the chemicals in Fraction IV in commercial kava. ... Flavokawains A, B, and C, three components detected in Fraction IV, demonstrated much higher toxicity against liver cells [i.e. higher than kavalactones], consistent with the high toxicity of Fraction IV against liver cells."

So, it is important to note that the "commercial kava" they used was Gaia ethanol extract, which when this article was written in 2009, was likely made from tudei.

Here's an earlier article by Xing, with full text (this article was written before the DHM and methysticin articles):
http://cancerpreventionresearch.aacrjournals.org/content/1/6/430
which has this bit:
"Currently, we do not know the identity of the chemopreventive candidates in kava. ... Among the different components in kava, the kavalactones seem to be the most potent inhibitors against cytochrome P450s (58). With respect to suppressing NF-κB activation, flavokawains A and B are the most potent compounds (18). The kava lactones and flavokawains are all potentially chemopreventive, some of which are under evaluation."

This was a study in mice, and they also note that the mice's livers were OK:
"Kava treatment alone also did not affect liver weight or enzymatic levels of ALT, AST, and GGT"

Conclusion:
"In conclusion, the results from this study clearly show that oral consumption of kava effectively reduced lung tumor multiplicity induced by NNK and B[a]P in the A/J mouse model, mechanistically through induction of apoptosis and suppression of proliferation possibly via inhibition of the NF-κB pathway. Furthermore, our preliminary data are not suggestive of hepatotoxicity. This study, for the first time, established the chemopreventive activity of kava against lung tumorigenesis. Combined with its strong epidemiologic data, kava is a promising chemopreventive agent against human lung cancer warranting further evaluations. At the same time, the safety of kava, especially with regard to hepatotoxicity, needs to be rigorously examined in vivo before any clinical evaluation."

 

[Zac Imiola (Herbalist)]

Now if they isolate the compound that is responsible and find the mechanism of action behind it, now that is good stuff.

I think this is helpful at understanding cancer. But not treating it. As @verticity said it could simply just kill cancer and healthy liver cells in doses that work.

I think traditional kava beverage has an affinity for the lungs and protective effect against tobacco.
This can be called a specific indication in eclectic medicine. Western herbalism is based on this.

I don't know if it can be used when cancer is already in someone's body... that's never been shown true

 

[Deleted User01]

@verticity, you ain't gonna believe this, but I was thinking about cancer vs kava yesterday (it happens as you get older). I was wondering if the anti-inflammatory properties of kava might help prevent cancer. Or ... could it be stress reduction that helps .... or could it be the diet of kava drinkers ... or the fact that most of us are very health conscious? Or all off the above. But can it fight an existing cancer? Well if it could, Kava would skyrocket to 1000 dollars a pound. I can see that all the evidence you present does point to Tudei being more toxic to the liver than noble. But everyone can make their own choice. There is a reason the code name for Tudei is "weekend kava" and not "everyday kava".
Thanks for all the great research. I hope you are posting this info on your excellent web site.

 

[PepperyPyrone]

Now if they isolate the compound that is responsible and find the mechanism of action behind it, now that is good stuff.

I think this is helpful at understanding cancer. But not treating it. As @verticity said it could simply just kill cancer and healthy liver cells in doses that work.

I think traditional kava beverage has an affinity for the lungs and protective effect against tobacco.
This can be called a specific indication in eclectic medicine. Western herbalism is based on this.

I don't know if it can be used when cancer is already in someone's body... that's never been shown true

Yes, even some of best antineoplastic compounds used in pharma phase 1/2 studies in humans don't make the cut due to toxicity or lack of efficacy compared to what was shown in vitro. In vivo is always a whole other story. @Mrbinx69 True. Just because science can explain the mechanism of action of a compound doesn't mean it will work as a drug to eradicate a primary tumor (especially metastatic secondary tumors) in vivo. Also, it really depends on what type of cancer it is, as the type of cancer cell (oncogenes at work and what signaling pathways) predicts treatment response. But it would be interesting to know if injecting Flavokawain A/B into certain tumors would kill it by itself as shown in vitro. Maybe someday they will test this in vivo in mice to get a glimpse of its potential but as of right now with the current literature out there, they are just skimming the surface with its possible preventative effects, but at least its a start. I think there is enough preliminary evidence in bladder, prostate, breast, lung and colon cancer cells with the known pathways involving DR5, BIM, BCL2, BAX, JNK, and NF-KB to get funding to look at in vivo studies. But also as @verticity pointed out, there could easily be other unknown compounds at play here outside of flavokawains and kavalactones.

@verticity , yes, haha, this is the paper I was talking about, thanks for pointing out where I saw that on your forum page! Its a great in vivo study. https://www.ncbi.nlm.nih.gov/pubmed/27728767

 

[Deleted User01]

Man, we got some serious science talk here. You guys keep it up, and the price of kava will skyrocket. Thanks guys for the great posts. I'm learning a lot and I'm also hopeful that Kava can guard us (even a little bit) against bad things invading our bodies.

 

[verticity]

...
@verticity , yes, haha, this is the paper I was talking about, thanks for pointing out where I saw that on your forum page! Its a great in vivo study. https://www.ncbi.nlm.nih.gov/pubmed/27728767

Do you have the full text for that one? I can't seem to find anything but the absrtact online.

 

[verticity]

Hey, it looks like they wrote a couple other DHM/cancer articles in other journals. Those guys are pretty prolific! I guess there is nothing else to do in Minnesota... Here are 2 with full text:
From 2014:
Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differentially reduces DNA damage in A/J mice
Abstract: "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."
March 2016:
Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification
Abstract: "Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM’s differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O-glucuronidated NNAL (NNAL-O-gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O-glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL-O-gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents."

 

[Alia]

Have we had similar discussions before on related "kava-as a cancer preventative"? Dr. Xing formally of University of Minnesota (now U. of Florida) has been key. But, also-- UC, Irvine-- Prostate Cancer Prevention, New York Botanical Garden w/ affiliates -- Colon and Breast Cancer. Many have tried to isolate specific parts of the kava "ingredients" even Methysticin has been suggested. My favorite is a quote from a highly qualified PhD from UH, Hilo College of Pharmacy --"Current literature and the preliminary data of the proposed research support the hypothesis the 'Awa (Piper metysticum) will inhibit the growth of cancer cells via a novel calcium-dependent mechanism". That's 'awa as a beverage, just as the NYBG study demonstrated. PS- the calcium mobilizing activities could not be duplicated with just extracts. So it is indeed a complicated activity.

 

[Deleted User01]

"A calcium-dependent mechanism", is that like a small child who needs his milk 3 times a day? Anyway, let's hope that kava is helpful for that. It could have been the new superfood/botanical if not for the negative press of the past. I read a list the other day that had tumeric, guaruan (or something like that), and a bunch of the usual suspects and still no kava on the list. Their loss.

 

[verticity]

Have we had similar discussions before on related "kava-as a cancer preventative"? Dr. Xing formally of University of Minnesota (now U. of Florida) has been key. But, also-- UC, Irvine-- Prostate Cancer Prevention, New York Botanical Garden w/ affiliates -- Colon and Breast Cancer. Many have tried to isolate specific parts of the kava "ingredients" even Methysticin has been suggested. My favorite is a quote from a highly qualified PhD from UH, Hilo College of Pharmacy --"Current literature and the preliminary data of the proposed research support the hypothesis the 'Awa (Piper metysticum) will inhibit the growth of cancer cells via a novel calcium-dependent mechanism". That's 'awa as a beverage, just as the NYBG study demonstrated. PS- the calcium mobilizing activities could not be duplicated with just extracts. So it is indeed a complicated activity.

Yup, there were a couple previous discussions of these studies here:
http://kavaforums.com/forum/threads/kava-study-does-kava-prevent-lung-cancer.1830
http://info.biotech-calendar.com/bi...rch-Shows-Potency-of-Kava-Against-Lung-Cancer

In this thread you listed a bunch of references, some of the same ones mentioned above, and also some additional ones:
http://kavaforums.com/forum/threads/kava-and-lung-cancer.8654/

Maybe the admins here ought to organize all this stuff into a "megapost"...Megathread? .. Eventually I'll do something similar on my Mini-Me forum...

 

[Zaphod]

What about this? Are we trading lung, colon, and breast cancer for liver, kidney, eye and pancreas cancer?

"Conclusions We conclude that kava kava extract caused cancers of the liver in male and female mice. Increased incidences of testicular tumors in male rats might have been related to kava kava exposure. Kava kava also caused increased incidences of lesions in the liver, forestomach, kidney, eye, and pancreas of male and female rats, in the liver of male and female mice, and in the forestomach of female mice."

https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr571.pdf

 

[verticity]

What about this? Are we trading lung, colon, and breast cancer for liver, kidney, eye and pancreas cancer?

"Conclusions We conclude that kava kava extract caused cancers of the liver in male and female mice. Increased incidences of testicular tumors in male rats might have been related to kava kava exposure. Kava kava also caused increased incidences of lesions in the liver, forestomach, kidney, eye, and pancreas of male and female rats, in the liver of male and female mice, and in the forestomach of female mice."

https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr571.pdf

That is interesting, but a couple things to keep in mind:

- As far as I can tell, that study used inbred strains of rats and mice that are more susceptible to cancer than normal rodents (and also more susceptible to cancer induced by chemicals):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246016/
"When using specifically susceptible mouse strains such as the B6C3F1 hybrid, relatively high and variable incidences of liver tumors can occur in the untreated or vehicle control mice."
Maybe @PepperyPyrone would know more about that..

- They fed these inbred rodents massive overdoses of kava extract. The study used 0.125 - 2 grams of extract per kg of body weight. For a 75 kg person that would be like eating 10 - 150 grams of concentrated extract every day. Even when they did this for 2 years, the survival rate was the same as the controls; so actually I'm a bit surprised they weren't able to kill more of them...

So this study is interesting as it shows the extremes, by demonstrating how susceptible animals respond to huge overdoses, but I don't know how relevant it is to human beings drinking normal amounts of kava...

 

[Alia]

What about this? Are we trading lung, colon, and breast cancer for liver, kidney, eye and pancreas cancer?

"Conclusions We conclude that kava kava extract caused cancers of the liver in male and female mice. Increased incidences of testicular tumors in male rats might have been related to kava kava exposure. Kava kava also caused increased incidences of lesions in the liver, forestomach, kidney, eye, and pancreas of male and female rats, in the liver of male and female mice, and in the forestomach of female mice."

https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr571.pdf

I remember when this was 1st published and all the UH academics commented almost verbatim what @verticity has written. Also, "Kava kava extract was obtained from Cosmopolitan Trading Co. (Seattle, WA) in one lot (9077SDK), which was received in several batches". I am not sure if solvents are used in their method. Interesting that when I read through other studies devoted to preventing cancers (in mice) by giving them kava they say- "No evidence of liver damage was detected in animals consuming kava".
I also just read that 2016 paper on DHM blocking tobacco carcinogen and they say-
"It was also observed that DHM at 0.2 or 0.05 mg/g of diet,
while retaining the complete chemopreventive effect, did not
cause any induction of CYP1A1/2 activity in the liver
microsome. DHM therefore has a decent therapeutic window
to effectively block lung tumorigenesis without enhancing
CYP1A1/2 activity"

 

[PepperyPyrone]

That is interesting, but a couple things to keep in mind:

- As far as I can tell, that study used inbred strains of rats and mice that are more susceptible to cancer than normal rodents (and also more susceptible to cancer induced by chemicals):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246016/
"When using specifically susceptible mouse strains such as the B6C3F1 hybrid, relatively high and variable incidences of liver tumors can occur in the untreated or vehicle control mice."
Maybe @PepperyPyrone would know more about that..

- They fed these inbred rodents massive overdoses of kava extract. The study used 0.125 - 2 grams of extract per kg of body weight. For a 75 kg person that would be like eating 10 - 150 grams of concentrated extract every day. Even when they did this for 2 years, the survival rate was the same as the controls; so actually I'm a bit surprised they weren't able to kill more of them...

So this study is interesting as it shows the extremes, by demonstrating how susceptible animals respond to huge overdoses, but I don't know how relevant it is to human beings drinking normal amounts of kava...

@Zaphod brings up a good point, but @verticity and @Alia countered it well. I only worked with nu/nu nude mice in my work, of which does not have an immune system to fight off subcutaneous injected cancer cells, it's a great mouse model for studying metastasis. The B6C3F1 mouse is mostly used for toxin research and carcinogen work. Because they are not normally prone to spontaneous cancers outside of liver cancer they are a good model for looking at environmental/industrial carcinogens and oncoviruses. But they are known to develop liver cancer. I'm not really sure why they chose this mouse model if it was already prone to liver cancer. In this case it does look like kava could have increased their already high sensitivity to liver cancer, which is not a normal model and was not seen in the F344/N rats. Only the male F344/N rats had "marginal" increases in the incidences of testicular interstitial cell adenoma. If it was anywhere near significant why did they not do a meta-analysis study for testicular interstitial cell adenoma in humans? Maybe they did and didn't find anything? @verticity "They fed these inbred rodents massive overdoses of kava extract. The study used 0.125 - 2 grams of extract per kg of body weight. For a 75 kg person that would be like eating 10 - 150 grams of concentrated extract every day. Even when they did this for 2 years, the survival rate was the same as the controls; so actually I'm a bit surprised they weren't able to kill more of them..." ----- Yeah me too!

 

[Zaphod]

That is interesting, but a couple things to keep in mind:

- As far as I can tell, that study used inbred strains of rats and mice that are more susceptible to cancer than normal rodents (and also more susceptible to cancer induced by chemicals):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246016/
"When using specifically susceptible mouse strains such as the B6C3F1 hybrid, relatively high and variable incidences of liver tumors can occur in the untreated or vehicle control mice."
Maybe @PepperyPyrone would know more about that..

- They fed these inbred rodents massive overdoses of kava extract. The study used 0.125 - 2 grams of extract per kg of body weight. For a 75 kg person that would be like eating 10 - 150 grams of concentrated extract every day. Even when they did this for 2 years, the survival rate was the same as the controls; so actually I'm a bit surprised they weren't able to kill more of them...

So this study is interesting as it shows the extremes, by demonstrating how susceptible animals respond to huge overdoses, but I don't know how relevant it is to human beings drinking normal amounts of kava...

Fair enough. I agree with your review of the study. However, we (as a kava community) should make sure we are putting the same critical analysis & critique against the anti-cancer studies as this one. I am not a huge fan of the "superfood" movement that is mostly a marketing ploy (like pomegranate juice).