April 2007 (oldest post first). After reading the Delano Report a few months ago, I decided to test quercetin. For details (and a link to the report), please see my April 20th blog post titled Protocol, Spelled Out.

Quercetin is a flavonoid found mainly in apples, onions, berries, cauliflower and nuts. It has significant anti-inflammatory and antioxidant properties.

From Wikipedia: Quercetin may have positive effects in combating or helping to prevent cancer, prostatitis, heart disease, cataracts, allergies/inflammations, and respiratory diseases such as bronchitis and asthma. In fact, last August I bought a couple of bottles of quercetin for my asthma but hadn’t yet opened them. Until I read the Delano Report, that is. Then my interest in quercetin went way beyond asthma! An aside: I can report that my asthma is officially GONE. I still take one puff of my cortisone inhaler before going to bed, but that is merely a precaution.

MM and WNT. For the following section on WNT signaling pathways, I am greatly indebted to Stephen Martin, Ph.D., of the Grouppe Kurosawa. Without his posts, I might not have done any research on this topic. Last year, he wrote that WNT signaling is elevated in many cancers, including MM. Researchers have discovered that aberrant WNT signaling causes MM cells to proliferate and grow, as these studies show: http://tinyurl.com/2rorm6 and http://tinyurl.com/2yp3yc A Dutch study is currently looking into the WNT-MM connection, see: http://tinyurl.com/2ex6tp These signaling genes seem to be in every single type of cancer, from colorectal to oral cancer. For a detailed explanation on how they affect different types of cancer, see this important 2000 study: http://tinyurl.com/2jrw3p

What IS the WNT signaling pathway? In a nutshell, it is a complex network of proteins involved in many development processes (cell-to-cell communication during embyrogenesis). However, it can also influence cancer growth, as I mentioned. The more scientifically-minded can check out a Stanford University WNT Homepage containing a ton of information on the WNT gene: http://tinyurl.com/27fnajWhat is relevant to my research, however, is that this pathway is consistently active in MM and causes cell proliferation and growth. Not a good thing! And guess what? Quercetin inhibits it. An April 2007 Blood study examines acute lymphoblastic leukaemia (ALL), not MM, that is true, but what is significant is that quercetin inhibits the WNT signaling pathway and causes the ALL cells to self-destruct: http://tinyurl.com/2m5w2d More evidence can be seen in a second study printed in the same edition of Blood : http://tinyurl.com/3d34vm Again, ALL cells self-destructed when treated with quercetin. Does this mean that it would have the same effect on MM cells? I haven’t found any studies on quercetin and MM, specifically yet. But I have the feeling the answer is a resounding Yes!

My own observations. I have noticed two big changes since I began taking quercetin capsules more than a couple of months ago. One is that my rosacea (also known as curse of the Celts !) has gotten much better. I hadn’t connected this improvement to the quercetin, but recently I came to wonder: what else could it be? The other is that my peripheral neuropathy has gone completely. It had partially returned last fall (2006), though nothing like what I experienced in the pre-curcumin period (2005). Again, it’s impossible for me to say if the two things are related to my quercetin intake. Just a suspicion on my part. Of course, NOT to be discounted is the recent drop in my IgG count!

A note on quercetin from Wikipedia: Foods rich in quercetin include apples, tea (Camellia sinensis), onions (higher concentrations of quercetin occur in the outermost rings), red grapes, citrus fruits, broccoli & other leafy green vegetables, cherries, and a number of berries including raspberry, bog whortleberry (158 mg/kg, fresh weight), lingonberry (74 and 146 mg/kg), cranberry (83 and 121 mg/kg), chokeberry (89 mg/kg), sweet rowan (85 mg/kg), rowanberry (63 mg/kg), sea buckthorn berry (62 mg/kg), crowberry (53 and 56 mg/kg), and the fruit of the prickly pear cactus. A study by the University of Queensland, Australia, has also indicated the presence of quercetin in varieties of honey, including honey derived from eucalyptus and tea tree flowers.

This is just a first instalment. My research on quercetin continues. There is a lot to uncover, yet.

Higher levels of quercetin in organic tomatoes.

July 13 2007 post: I found a recently published University of California-Davis study (http://tinyurl.com/3dbb7d) particularly interesting because it compared the amounts of two flavonoids, quercetin and kaempferol (the latter is extracted from tea, broccoli and grapefruit, e.g.), in dried tomato samples that had been collected between 1994 and 2004 as part of a long-term study on agricultural methods. Researchers compared organic versus non-organic tomatoes. And, quelle surprise!, the organic samples had higher levels of both compounds, respectively 79% and 97%, than the non-organic ones. Science may finally be catching up to plain common sense.

According to these Duke researchers, attempts at inhibiting this mutated form of the RAS gene have failed so far. Therefore, they looked at inhibiting the cytokine activated by oncogenic RAS, and guess what? That cytokine just happens to be Interleukin-6 (yes, our infamous pro-inflammatory IL-6!).

The Duke University researchers also found that angiogenesis was reduced by inhibiting the production of IL-6, and that ‘IL-6 was like the gas pedal driving the growth of tumors,’ Counter said. ‘No gas, no growth, which is exactly what we saw when we inhibited IL-6 in tumors.’ Counter is encouraged that even though these findings are in cell culture and animal models, therapies based on targeting IL-6 in cancers driven by the ras oncogene could be tested in humans in the near future. […] A phase II trial is underway testing a monoclonal antibody against IL-6 for patients with multiple myeloma, a cancer that depends on IL-6 but is not known to have a connection to the ras oncogene. If the results of this trial are positive, studies might begin in ras-dependent cancers. Counter’s group is actively pursuing the idea that such an antibody may inhibit pancreatic cancer growth in mouse models. If these results are positive, this will open the door for Duke oncologists to organize a clinical trial to test the agent in human cancer patients. The abstract of the Duke study can be read here: http://tinyurl.com/23merm

The question then arises: is oncogenic RAS present in myeloma? As you may have guessed from the above-mentioned Duke Medical news release, the answer is: yes, it is, in a certain percentage of patients which seems to vary from study to study. Not surprising, I would add, since we are all so different. A 1992 study (http://tinyurl.com/ytb863) showed that RAS gene mutations were present in 47% of the MM patients (14 out of 30 patients). I thought the following finding was significant: RAS gene mutations were more frequently observed in patients with fulminating disease (10/15, 67%) than in patients with less aggressive forms of the disease (4/15, 26%). So, oncogenic RAS seems to be connected to a more aggressive form of MM. This would appear to be confirmed by the results of a 1989 study (http://tinyurl.com/yux83g): “While the mechanism of occurrence and biological role of ras activation in MM remains to be elucidated, the preliminary correlations observed in this study between the presence of ras oncogenes and poor therapeutic response suggest that further investigations of the possible prognostic significance of these alterations are necessary.”

According to a more recent Italian study, published in March 2007 (http://tinyurl.com/2bfugg) Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). These mutations were detected in 20% of 81 newly diagnosed MM patients. The abstract concludes, however, that these mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities. Another study, published in Blood in 2003 (full study: http://tinyurl.com/23e48r), looks at pathways activated by oncogenic ras that may stimulate IL-6-independent growth, and concludes: “In summary, we have identified several signal pathways in myeloma cells constitutively activated by expression of mutated ras genes. Our results also suggest that these pathways provide excellent molecular targets for future therapy.”

Why am I writing about this today? Because I just finished reading a study titled “Quercetin mediates preferential degradation of oncogenic Ras and causes autophagy in Ha-RAS-transformed human colon cells” and published in “Carcinogenesis” in May 2007 (abstract: http://tinyurl.com/22byoz; full text: http://tinyurl.com/23clc8) showing that quercetin downregulates the levels of oncogenic RAS in cancer cells. How about that? The study suggests that quercetin be used in cancers with frequent mutations of RAS genes. Interestingly enough, quercetin inhibits oncogenic RAS but not normal RAS. Excellent. Sure, this study is about colon cancer cells, but I think the implications could apply to MM as well, given the IL-6 connection. Therefore, I believe we MMers have another GOOD reason to keep taking quercetin (or to start taking it!).

November 10 2007 post: I recently read a study with a very long title, The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells (!), published in the European Journal of Pharmacology in February of 2007. The abstract can be seen here: http://tinyurl.com/26yy5q I was able to read the full study thanks to a friend (grazie, Sherlock!). As usual, I would be more than happy to forward the study upon request.

First, what are Chang liver cells? The online Dictionary of Cell and Molecular Biology tells us that these liver cells are derived from non-malignant human tissue. Now, I don’t want to get involved in a detailed explanation concerning inducible nitric oxide synthase, or iNOS, which is beyond my purpose here, anyway (phew!!!). Let it suffice to say that iNOS is linked to inflammation, and anything that inhibits it is good news. We already know about COX-2 (see my Ellagic Acid and Natural COX-2 Inhibitors Pages for more info) and CRP, and of course the ubiquitous NF-kappaB. Ah yes, and kaempferol is a natural flavonoid found in tea, broccoli, grapefruit and other plant sources. On with the study, then.

On page 222 we read that Reactive C-protein (CRP) is an acute phase protein produced by hepatocytes whose serum elevation is considered as indicator of chronic inflammation and whose interaction with endothelial cells may be the mechanistic link between CRP and atherosclerosis [ ]. It is known that IL-6 induces CRP through a mechanism involving NF-kappaB, but no study has until now documented potential effects of flavonoids on CRP expression in liver cells. Hepatocytes, by the way, are liver cells (for the more scientifically-minded, epithelial cells found in the liver that, among other things, have the function of helping to detoxify our blood).

Both quercetin and kaempferol reduce iNOS and COX-2: The present study indicates that both flavones reduce iNOS protein level in activated Chang Liver cells and that kaempferol was a slightly more potent inhibitor at low concentrations. COX-2 protein level was also reduced. And, most importantly for our purpose, i.e., identifying substances that reduce CRP levels naturally: Our data show that both quercetin and kaempferol significantly reduce CRP protein level in liver cells and that this inhibition is concentration-dependent [ ]. SIGNIFICANTLY REDUCE? Well, I have been putting quercetin powder in my curcumin/chocolate mixture for other reasons (see my Bioavailability page for more information), but I am very pleased to discover that it may also be reducing my CRP levels.

The study ends: In summary, the present study indicates that the modulation of iNOS, COX-2 and CRP by quercetin or kaempferol may contribute to the anti-inflammatory effects of these two structurally similar flavonoids in the liver, via mechanisms likely to involve blockade of NF-kappaB activation. Sounds good to me!

Important aside. After reading this study, I must post a warning: at very high doses, quercetin MAY have some genotoxic effects, see http://tinyurl.com/2lzaw6. The words to keep in mind are may and very high doses. Low doses of quercetin are okay, and I have confirmed this elsewhere (see for instance: http://tinyurl.com/2uvbzt). I have been taking a maximum of two grams per day. Not much, so I am not in the least concerned and will continue to take my daily dose, but it reminds me that caution is the name of the game, as the saying goes. So, do your research first!

According to the Times UK July 5 online edition (http://tinyurl.com/2pu5zq), these researchers believe that the different levels of flavonoids in tomatoes are due to the absence of fertilisers in organic farming. Plants produce flavonoids as a defence mechanism; they are triggered by nutrient deficiency. Feeding a plant with too many nutrients, such as inorganic nitrogen commonly found in conventional fertiliser, curbs the development of flavonoids. The lower levels of flavonoids in conventional tomatoes were caused by over-fertilisation , the research team concluded. So a rich soil may actually not be such a good thing to have in our vegetable garden, after all! Interesting.

July 19 2007 post (update): I have just linked a couple of news items on quercetin and oncogenic RAS whose consequences may be significant to us MMers. Before I go on, though, what is this RAS business? Simply put, RAS is a gene that can mutate and become overactive, leading to the development of cancer. In this dangerously altered state, it is known as oncogenic RAS, and is present in almost one-third of all cancers, according to a recently published Duke Medical news release, see http://tinyurl.com/3wurzq 

September 2 2008 post: This morning I read some of the PubMed Alerts that I received during my absence. One of them led me to the abstract (see: http://tinyurl.com/5wrw5p) of a recent study on quercetin and prostate cancer cells published in “Prostate” at the end of August.

October 16 2011 post. Today I read the abstract of a recent study showing a new (“new” to me, that is…or perhaps I simply couldn’t remember it!) anticancer activity of one of my staple supplements: quercetin. It turns out that, among its many other positive anticancer effects, quercetin also inhibits proteasomes, just like curcumin and bortezomib (= Velcade). See: http://goo.gl/HHIqk

I have a Page here on quercetin, but I haven’t updated it in years. Very remiss of me, especially since this is such good stuff! Sooo, what is it?

Quercetin is a flavonoid, that is, a plant chemical with significant anti-inflammatory, antiviral and antioxidant properties, and possibly antihistamine effects, which we can find in red apples, broccoli, onions, berries of all kinds, cauliflower, green tea, grapes, red wine and nuts. An average adult in the Western world probably gets 25-50 mg a day of dietary quercetin. So yes, it’s already in our diet, especially if we eat lots of the above-mentioned stuff.

Problem: I remember reading a study (no time to look now for the reference, so take this with a grain of salt) showing that very high doses of quercetin are toxic to male rats in the long run. But these were superboomamazingly high doses, and by now you must know what I think of HIGH DOSES of practically anything!!!   At any rate, that is the reason why I stick to just 1.5 grams of quercetin a day, which is not very much at all…

TWO MORE WARNINGS:

1. those who take bortezomib should NOT also take any quercetin supplements. See:http://goo.gl/rOG3q. Quercetin apparently can interfere, via a bunch of chemical reactions, with bortezomib’s anti-myeloma activity. Not good at all! However, please note that this interference diminishes, according to tests carried out in this study, when myeloma cells get preincubated with quercetin before being exposed to bortezomib, indicating a direct effect of quercetin on myeloma cells. And this interfering effect was also reversed with supplemental inorganic boric acid. Still, it’s best to be cautious. If I were on bortezomib, I probably wouldn’t take any quercetin. Just like I wouldn’t drink any green tea. Not on my Velcade days, that is. However, those of us who aren’t on bortezomib shouldn’t have any problems…

2. It also should NOT be taken with fluoroquinolones, which are heavy duty antibiotics that treat pneumonia, acute sinusitis and genitourinary infections. This is a class of antibiotics known as “chemotherapeutic bactericidal drugs,” so, hey, you can tell by those three words that we’re talking serious stuff, here. Not our usual tetracyclines, I mean…Anyway, from what I read online, these antibiotics can be incredibly toxic, to the point of damaging our mitochondrial DNA. Gulp. Not surprisingly, many of  ’em have been removed completely from clinical use, except, interestingly for animals (figures!)…If you go to Drugs.com, e.g., you will see that the info on fluoroquinolones has been “archived.” There you go. So, since we will probably never ever go within an inch of a fluoroquinolone, we have nothing to worry about…Still, I thought I should report it…you never know…

Okay, now that we have all (!) the warnings out of the way, let’s get to the reason why I’m posting about quercetin today. Well, yes, it’s because of the above-mentioned study, whose abstract provides us with enough information to go on:

1. quercetin exterminates epithelial cancer cells. Zip zap…dead…gone forever.  (Note: epithelial cells line our entire body, they are in our guts and so on, and epithelial cancer is perhaps better known as carcinoma, which accounts for 80-90% of all cancers, including breast, colon and prostate…)
2. it blocks mTOR activity. Now, mTOR, which is (by the way) the main target of the chemo drug rapamycin, is a really nasty pathway involved with myeloma disease progression. When mTOR is activated, you see, MM cell lines resist being killed. Unmistakably, a very bad thing. And in fact, if you look at PubMed, mTOR inhibitors are being developed all over the place to treat myeloma…For example, here is a study on lenalidomide coupled with an mTOR inhibitor:http://goo.gl/k3FrX
3. autophagosome formation: for me, reading this part (= the middle part of the abstract, mostly) was like reading a treatise in ancient Hungarian, so at some point I guess I’ll have to find and read the full quercetin study to see if I can understand what’s happening. Note: I did read in other PubMed studies that mTOR regulates autophagy. But that didn’t help my non-scientific brain to process this stuff…not really…However, I have an inkling that it’s all related to proteasome inhibition, thus it should be a good thing, but hey, I’m not 100% sure…
4. last but certainly not least!, the ability of quercetin to inhibit proteasomes: proteasome inhibition by quercetin can be regarded as a major cause of quercetin-induced cancer cell death. Major cause, eh? Sounds good to me!!! 

Could it really be that an apple (red apple!) a day could help keep the myeloma specialist away?