Fresh article on Berberine's positive effect on CLL

[Vlaminck]

"Anti-tumor effect of berberine on chronic lymphocytic leukemia cells." Couldn't read the whole article without paying for it (should be a law), but the abstract discusses beneficial changes to CLL cells from taking the supplement berberine. Thought might be of some interest.

link.springer.com/article/1...

[SeymourB]

Vlaminck -

Appears to be in-vitro research.

I found a different in-vitro study with full text results:

ncbi.nlm.nih.gov/pmc/articl...

Berberine affects mitochondrial activity and cell growth of leukemic cells from chronic lymphocytic leukemia patients

Further in is a discussion indicating that berberine enhances the effect of Venetoclax:

"Combination index (CI) curves and isobolograms computed by the Chou–Talalay model (CalcuSyn software, Biosoft, Cambridge) from dose–effect profiles of activated leukemic cells treated for 42 h with increasing concentrations of BRB (1–10 μM), ABT-199 (10–100 nM) or BRB/ABT-199 at constant ratios. CI measures drug interaction effects: additive: 0.9 ≤ CI ≤ 1.1, synergism: CI  1.1. "

I don't understand all that, to be honest. But I'll note that they are not specifying doses, they are specifying concentrations in uM and nM (micro Molar and nano Molar), with 1000 times the concentration of berberine to venetoclax.

Also, berberine does affect normal lymphocytes:

"Normal B lymphocytes were less sensitive to the alkaloid cytotoxic activity (Fig. 1D). Cell viability was totally unaffected at the doses that induced apoptosis in CLL cells. Cell proliferation of normal B cells was partly inhibited when BRB was present during the initial activation stages, while it was virtually unaffected when BRB was administered later on, i.e. on cells already in overt proliferation (Fig. 2D). This observation suggests that BRB might affect normal lymphocyte preferentially during the early stages of mitogenic stimulation while clearly proliferating cells remain resistant to its cytostatic effect."

They compare it to dosages used for hypercholesterolemia and diabetes:

"BRB is a well-tolerated drug at the doses used for hypercholesterolemic and diabetic patients (1–2 g/die). At these doses the plasma concentrations of BRB and its bioactive metabolites is lower (10–50 nM) than the presently seen doses that displayed metabolic inhibition in our CLL cells [32]."

Again, that's 10 uM is 1000 times the dose the lower dose listed for hypercholesterolemia and diabetes.

I found another study that mentioned toxicity testing, but for a different cancer:

sciencedirect.com/science/a...

Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways

The in-vivo tests were done on mice in section 2.9. Xenograft models in nude mice:

"BBR(5, 10 or 20 mg/kg body weight) was dissolved in 100 μL of vehicle solution (normal saline with 0.5% DMSO) and administered intraperitoneally every two days for a total of 14 days."

"The toxicity was assessed by lethality and weight loss in nude mice."

Compare that to dosage listed for diabetes:

healthline.com/nutrition/be...

"Dosage and recommendations

There’s currently no established dosage for berberine supplements.

However, most studies have administered 1,000–1,500 mg per day.

Berberine has a half-life of several hours, so it doesn’t last in your system for too long. Most berberine supplements contain 500 mg per capsule, and supplement labels often recommend taking berberine 3 times per day before meals (12).

This equates to taking a total of 1,500 mg daily."

Using the murine dosages, which may not be safe for humans, 5 mg/kg for a 100kg human tworks out to be 5000mg of berberine. and at the 20mg/kg murine dosage, it's 4 times more - 20000mg.

I'm not inclined to say this is at all safe at this level.

The final question might be does taking the diabetes dose orally do anything noticeable for CLL in-vitro - we'll have to keep digging to find such a study, and hope its well constructed.

WebMD has an article on berberine:

webmd.com/vitamins/ai/ingre...

There are a long list of drug interactions listed there.

=seymour=

[Vlaminck in reply to SeymourB]

Thank you, Seymour, lots of things to think about and links to review!

[Jm954 Administrator]

Isoquinolines are very crude agents which are used in the manufacture of dyes, paints, insecticides and antifungals. It is also used as a solvent for the extraction of resins and terpenes, and as a corrosion inhibitor and sounds very toxic. In the days of more targeted therapies, I'm not sure this has a place.

Jackie

[Vlaminck in reply to Jm954]

Berberine (one of the constituents of goldenseal and other medicinal plants) has been used in Chinese medicine for millenia. I have used it off and on, for other things (has so many medicinal uses) but not knowing it might have positive effects for CLL. You might find reading the article interesting. And gotta comment on your statement that "isoquinolines are very crude agents". They and their relatives are used in many medicines. Here, on quick google, a 2017 article on new antibiotic from isoquinolone alkaloid:

pubmed.ncbi.nlm.nih.gov/279...

[SeymourB in reply to Jm954]

Jm954 -

I do agree that targeted drugs are much more effective than the complex chemical compounds from naturally occuring herbal products. I wouldn't characterize berberine as merely another isoquinolone. Effective dose is everything. In-vitro doses are seldom achieved in oral drugs - that's why so many promising drugs fail.

I would also argue that raw herbal products can be contaminated in growing or processing. There's much less oversight of quality in herbals in most countries.

Batches of herbals also vary in characteristics because of weather and soil conditions. This also hampers research, since one lab's study of an herbal cannot be easily compared with another's because of variation in dosage between suppliers and even between harvests from the same supplier. So we get generalized data.

Herbals also have undiscovered adverse effects and are not tested thoroughtly for adverse effects because of an unwarranted assumption of natural safety. So I welcome research that looks at toxicity at a range of dosages. The paper I linked to did some of that, but since it was in-vitro testing using B-cells, they could only look at toxicity against B-cells and not other cell types.

On the other hand, new medicines come from existing chemicals, some of which come from plant or animal cells. Some small molecule(s) derived from berberine may prove to be the useful addition to existing targeted drugs. I did like that the paper I looked at tried to examine potentiating the effect of venetoclax, and the focus on venetoclax resistance. I wouldn't say that they solved the problem, though. Still many steps to go through.

=seymour=

[Vlaminck]

Getting negative feedback re this article, let me emphasize that I am not posting so that we all go out and start gobbling berberine. Instead, it is possibly of interest to this community and they might want to discuss with their doc or do further research, or keep their eye on it, or ignore. I hope others will post recent (scientific, such as NIH) articles on compounds showing promise. And that's all this does.

[flipperj in reply to Vlaminck]

Interesting. I have had great success using berberine to treat GI tract infections. Unfortunately cheap natural means to maintain health have fallen out of favor in today’s pharmaceutical based healthcare environment.

[Vlaminck in reply to flipperj]

Yes, even tho the majority of moderns medicines are either directly taken from or heavily inspired by these cheap, natural products (metformin -- goat's rue, aspirin -- willow tree bark, all opiates -- poppies, breast cancer vinblastine from periwinkle, etc etc)

[SofiaDeo in reply to Vlaminck]

I don't think pharmacognosy (study of plants and other natural substances as sources of drugs) is a required class anymore, like when I took it.

[Big_Dee in reply to Vlaminck]

Hello Valminck

I found it an interesting article

[Vlaminck in reply to Big_Dee]

Thank you, Big_Dee

[CycleWonder]

I was concerned that I read berberine can interfere with blood clotting. This may be an issue for someone with low platelets.

[Vlaminck in reply to CycleWonder]

Yes, for sure. In fact, so many of what i consider to be healthy nutriceuticals also have that effect. Vitamin E does that to a degree. So if that is an issue, definitely skip or talk to doc. Everything has to be in balance.

[CycleWonder in reply to Vlaminck]

The reason I noted the clotting effects of berberine is because many people with CLL have low platelets at some point in the progression of the disease.

[Vlaminck in reply to CycleWonder]

Very relevant because you are right.

[steve_canada in reply to Vlaminck]

It seems that anytime a natural remedy is mentioned - the idea is shot down by many people including the wealthy drug companies.

Vlaminck has relayed to us a credible study that shows promise.

I found an interesting read and may start taking it. At this point I’m basically a science experiment for the oncologists.

Cheers and keep learning…

labroots.com/trending/cance...

[CycleWonder in reply to steve_canada]

We post unwanted side effects about various meds as well. It’s useful to be aware of side effects from both natural remedies and medications.

[unairdefamille in reply to steve_canada]

Yep! Aren't we all! I agree with everything you said. May we all be successful experiments with positive outcomes 😊

[SeymourB in reply to steve_canada]

steve_canada -

Valid points. I'd say that biases are the enemy here - both in favor and against.

I would hasten to add that nutraceutical companies are wealthy, and shut down ideas too. Ever see a negative testimonial on a nutraceutical web site? Ever see progression free survival or adverse event numbers?

We with CLL get focused on the WBC and ALC numbers to the exclusion of all else. Measuring lymph nodes and spleen are harder. So what will your criteria be for success or effect? How will your experiment be shared? What brand or supplier do you

I'm sure you do your research, as evidenced by the link you posted. I'm no longer early in my Watch and Wait. I tried turmeric for a short time with disastrous results only somewhat unique to me. I looked at the EGCG studies, and concluded that I could not achieve the dosages necessary. I do drink green tea and matcha occasionally, but I'm sure it's not enough to make a difference.

=seymour=

[Vlaminck in reply to SeymourB]

Sorry you had bad results from turmeric. I take turmeric and green tea extract (on different days), but not at the dosages I've seen referenced. The green tea can upset my stomach and I have a kidney stone tendency which is why I don't take a strong dose of turmeric. I take a lot of nutriceuticals but none in huge doses. But still open to learning more.

[SeymourB in reply to Vlaminck]

Vlaminck -

For me, turmeric caused a gallbladder attack that led to a cholecystectomy. My blood tests have never been the same - monocytosis and neutrophilia. But I'm not sure the turmeric caused that. I ate the turmeric because I had a sinus infection. It could be I caught a bug that's lasted 4 years now. or that my B-cells caught a second mutation that makes me even more susceptible to autoimmune or infectious disease. But I don't usually have a fever.

I'll eat turmeric, especially in Indian cuisine. I drink green tea or matcha occasionally, too. I just think the benefits are way overhyped.

=seymour=

[AussieNeil Administrator in reply to steve_canada]

Vlaminck, we last discussed berberine a year ago: healthunlocked.com/cllsuppo.... SofiaDeo provided some useful feedback and I noted we only had mouse model studies and that the synergistic effects with BCL-2 drugs (venetoclax) might show promise.

Steve, like the study Vlaminck referenced in her post, this berberine study you referenced was an in vitro study. What's more, it only gave mild results when used in conjunction with another CLL candidate drug, (which I couldn't see mentioned. I wonder if it was a BCL-2 inhibitor? ). "They attempted to use berberine in conjunction with another chronic lymphocytic leukemia drug candidate with mild results. Never the less, berberine represents a possible pathway for new therapeutics in treating similar cancers that do not undergo the Warburg Effect."

Lots more work to be done to get effective results, with a yet to be established dose for which we don't yet know whether it has potentially dangerous off target effects or drug interactions.

Drugs.com has an extensive section on berberine, including how it can interact with some drugs:

drugs.com/medical-answers/b...

"Berberine appears to have low toxicity at normal doses with stomach effects being the most common complaint; however studies are limited and doses are not well-defined."

Memorial Sloan Kettering Cancer Center herbal database also has significant coverage mskcc.org/cancer-care/integ...

Vlaminck, vincristine is another chemotherapy drug derived from the Madagascar periwinkle. It is marketed as Oncivin and is the 'O' in R-CHOP, which is our best current therapy for Richter's Transformation, for which we desperately need more effective treatments. Chris/CLLCanada highlighted that his Richter's Transformation R-CHOP treatment included two treatments derived from nature, highlighting the damage vincristine could do to his heart and noting he could only have one treatment with it. Chris successfully beat his RT but later had congestive heart failure. Per the introduction of this study from 2 years ago, researchers are still working on this limitation for vincristine based therapy. frontiersin.org/articles/10...

"Vincristine, a microtubule-destabilizing drug, is commonly administered as an effective anticancer agent for treating brain tumors, leukemias, lymphomas, and other solid tumors (Murphy et al., 2002; Pui and Evans, 2006; Van Den Bent et al., 2012). Vincristine’s better-known severe side effects that limit clinical utility include bone marrow depression, hyponatremia, peripheral neuropathy, and gastrointestinal distress (Cavaletti and Marmiroli, 2010; van de Velde et al., 2020; Geisler, 2021). However, in recent years, cardiovascular damage also has been described after vincristine treatments. The main cardiovascular side effects provoked by vincristine are myocardial ischemia and infarction, which tend to occur during or shortly after therapy and might therefore be related to coronary artery vasospasm as a result of cellular hypoxia (Meinardi et al., 2000). However, the vascular toxicity induced by vincristine is little studied."

Neil

[Vlaminck in reply to AussieNeil]

Thanks, Neil. I think it always helpful to be cautious, to note cautions, to consider such factors in studies as in vitro versus in vivo, etc. And thanks for mentioning the earlier discussion. I didn't explore that seeing that this study was only a couple months old. Hope everyone understands, and I suspect mosts do, that this is shared for those like me who are interested in what's out there and and what's being looked at in the natural world which is the frontier for most medicines. Following an article on high polyphenol olive oil, I am now taking that (just 1-2 tablespoons) because I also understand that olive oil is good for you anyway. Until more certainly, I tend not to take large doses of anything (well, except chocolate).

[MisfitK in reply to Vlaminck]

"Until more certainly, I tend not to take large doses of anything (well, except chocolate)."

I find such wisdom in this sentiment. Health, especially with CLL, tends to be a balancing act, so while in Watch and Wait, baby steps and moderation seem to always be the wisest steps for anything.

That said, I'm a big fan of using the best of eastern and western medicine or natural and pharmaceutical help when it comes to living my life. I just never do it above normal people doses, and without active blood monitoring with the hemo (from the beginning, he has had the list of things I do, and it's updated every appointment - he doesn't just want my single pharmaceutical prescription, but everything I take or do, including the afternoon green tea:).

[Notmuchenergy]

I always want to hear about this type of information. I have kept myself going for 14 years using supplements on W&W.

I haven’t enjoyed the best of health over this time, but the haematologists say that there is nothing they can offer me that will help. Unfortunately this is the same for many people in my position. People tend to think if you are on W&W, that you must be quite well. This definitely isn’t the case for many.

Of course we would take standard treatment if we were offered it but many of us just don’t fit the criteria

[Vlaminck in reply to Notmuchenergy]

Energy can be a challenge. I get good spells where I actually have "gym energy", meaning I could feel like going to a gym (in such a spell I signed up for a year) and then long periods when the very idea feels ridiculous. If I may say, do pay attention to Epstein Barr virus (EBV) which can reactivate with weakened immune systems and that caused me the most paralyzing fatigue ever had. Every so often I think I get a reactivation, not as bad but still. . . . Anyway, just another possible cause of fatigue to consider. I routinely take monolaurin which, among other health benefits, actually can tend to dissolve the lipid envelope in enveloped viruses, of which EBV and Covid are two.

[Notmuchenergy]

I take my blood pressure whenI feel exhausted and it seems to coincide with when my blood pressure is low.

I did have glandular fever when I was 20 and I remember how exhausted I felt with that