The opposite of what we knew…

February 20, 2010 / / 3 Comments

Do you remember all the hoopla caused by a June 2009 study on green tea and bortezomib? If not, please click here: http://margaret.healthblogs.org/life-with-myeloma/discovery-of-curcumin/curcumin-and-bortezomib/egcg-and-bortezomib That study came as very bad news for devoted green-tea-drinking patients on Velcade, even though, as Dr. Durie pointed out during a patient seminar that I attended last fall, those patients can still have their cuppa…just not on their Velcade days…

Now for today’s topic. Not too long ago, a blog reader (thanks!) reminded me of a November 2009 study that I had read in December but hadn’t posted about… Sherlock, grazie!, sent me the full study, whose main result is spelled out in the abstract (http://tinyurl.com/ydyaqca): EGCG is synergistic with bortezomib (=Velcade) against the KM3 multiple myeloma cell line. SYNERGISTIC??? That means that EGCG and Velcade are more efficient myeloma cell assassins when used together…

Wait a sec…in June we were told that EGCG antagonizes bortezomib (see: http://tinyurl.com/yfe24cl, full text also available for free)…this group of researchers found that not only was EGCG not toxic or (at higher concentrations) only mildly toxic to myeloma cells, but also it prevented bortezomib from doing its job. In other words, based on the June study, EGCG actually protected the myeloma cells…from bortezomib.

When I first read and posted about the June study, I don’t remember being bothered by the occasionally arrogant language used by the authors…especially in this excerpt about EGCG: this “miracle herb” extract is also consumed by many cancer patients who follow popular trends and self-medicate with complementary and alternative medicine (CAM) in hopes to support their conventional therapy or to lessen the burden of side effects—sometimes without the knowledge of their health care provider. “Popular trrrends”??? I say, I am feeling quite offended right now…how did I miss that condescending tone when I first read the study last year? Well, I suppose I was more focused on the importance of the issue at hand, i.e., warning Velcade-users against taking EGCG or even drinking green tea…

I also (!) didn’t question the finding that EGCG, when used alone, wasn’t able to kill even one miserable little myeloma cell, even at concentrations that are much greater than the typical concentrations achieved in humans. This is contrary, e.g., to the results of an authoritative 2006 study (see: http://tinyurl.com/yzsdu38)… Makes me wonder…

One more thing. I would like to point out that, incredibly, the online media paid no attention whatsoever to the November pro-EGCG study, whereas the complete opposite is true of the June anti-EGCG study…in fact, if you do a quick online search, you will still find warnings, even recent ones, about drinking green tea with bortezomib…even if you type the words “EGCG” “bortezomib” and “synergy.”

What you will not find (at least I did not) is the slightest mention of the November 2009 study, the one with the synergy results. That story just wasn’t picked up, for…some reason (I can only guess…). Well, today I decided to fill the gap…not because I think that the November study is a better one, that is not for me to judge!, but because I don’t think it fair that this study be so blatantly ignored…

Okay, for reasons of simplicity, from now Study A will be the June anti-EGCG with bortezomib study, and Study B will be the November pro-EGCG with bortezomib study.

Just a quick glance at the two studies showed that there were differences in caspase activation…In Study A, EGCG blocked the activation of caspase-7, which essentially stopped bortezomib from exterminating the myeloma cells. In Study B, instead, EGCG activated different caspases, specifically caspase-3, -8 and -9, leading to the death of the myeloma cells. Some day I should really look into this caspase business…until then I will not be able to figure out how, why or if this might be significant (I’d be glad for some help, here!)…

For lack of time, sorry, I am going to jump to the Discussion part of Study B. As I had hoped, this is where the authors compare their own results to the ones of Study A (identified as “they” in the following excerpts):

-They use a relative [sic] lower concentrations of EGCG (10 mM) and bortezomib (10 nM), whereas we used a relative [sic] high concentration of EGCG (25, 50, and 100 mM) and bortezomib (20 nM). So let’s see…Study A used a lower dose of EGCG and bortezomib, Study B a higher one. Okay, that is certainly a difference.

-We focused on the mechanism of EGCG inhibiting myeloma cell growth and inducing cell apoptosis potentiated by bortezomib, whereas they focused on the effect of EGCG on bortezomib in myeloma cells. So, we found that EGCG inhibits myeloma cell growth and induces cell apoptosis potentiated by bortezomib. This part wasn’t clearly worded, in my opinion (but it is true that I just got over a cold…is my mind still fogged by a bit of congestion?). In fact, I don’t see any difference at all…Mental note: I need to find the time to compare how the experiments were carried out in both studies.

-This may be because of different drug concentrations or different cell lines. Study A and B (and even the above-mentioned 2006 study, by the way) tested EGCG and bortezomib on different myeloma cell lines. And different doses were used in both studies. Is that enough to explain their differing results? Possibly.

I found myself wondering about the different myeloma cell lines used in different studies. Interesting topic. I had no idea that there were so many myeloma cell lines. I began doing some research but had to give up. Too complicated and time-consuming…

Well, I admit, I am still baffled. I suppose that I would still be cautious about taking green tea or EGCG with Velcade. I would follow Dr. Durie’s suggestion. Best to be cautious. Still, Study B gives us some (green) tea for thought and shows how much we still have to learn…

P.S. Here is a list of things that Velcade patients should avoid taking: http://tinyurl.com/yk2tclg

Mayo EGCG study

March 10, 2008 / / 34 Comments

Thanks to Don (see the link to his blog, Myeloma Hope, on the right), Sherlock and I found out about a 2005 Mayo Clinic study on EGCG (green tea extract, see my permanent page for more information). Sherlock looked it up and sent me the full study (abstract, 2006: http://tinyurl.com/29dyp5), which I read this morning. I almost cried with joy.

In a nutshell, after reading a Mayo in vitro report on EGCG’s annihilation of human CLL (chronic lymphocytic leukemia) cells, several Mayo (and probably non Mayo!) patients with CLL began taking this extract on their own. The researchers report that they became “aware of four patients with low-grade B malignancies,” who “appeared to have an objective clinical response.” Three of them achieved partial response (PR). I would like to note that their markers had been worsening before they began taking EGCG: “Several patients presented here had documented steady clinical, laboratory, and/or radiographic evidence of progression immediately prior to initiation of over-the-counter green tea products and then developed objective responses shortly after self-initiating this therapy.”

A "quick" parenthesis. During the discussion period at the NF-kB-curcumin-cancer conference on Saturday (see previous post), I was sitting up front with the other panel members, facing the audience. Next to me was a very nice doctor, I think a urologist (but wouldn’t bet my life on that). Well, in response to a question about why the Tuscan Regional Government doesn’t promote the use of curcumin, since it works for so many patients, scientific studies support its use in cancer treatment, AND it’s cheaper than many drugs, the good doctor answered, more or less, that science needs time, that anecdotal evidence is not scientific proof, that we have to wait until clinical trials are set up, the results published, blablabla. (I wish this cautious man had been on the Avastin committee, by the way!)

I waited until he had finished, took the microphone, and replied “you are right. Science needs time. But we are patients, cancer patients, and we don’t have that kind of time. If, for instance, I had waited for the results of the MD Anderson curcumin-myeloma clinical trial to be published, I don’t know how I would be doing right now. The first results from the trial were presented in December 2007, that is, almost two years after I began taking curcumin.” I forget what I added, but the tape should remind me (and perhaps slightly amend what I just wrote). At any rate, as I remember (!), he agreed that I was right.

Obviously, I am NOT suggesting that we (cancer patients) go out and try just ANYTHING. That would be absurd and dangerous. Beware of websites that tell you that they can cure your cancer! Avoid those like the plague.

But some substances, such as curcumin extracted from turmeric and EGCG from green tea, have been used for centuries to treat all sorts of ailments, as we know. So I am talking about "ancient" non toxic substances that have in recent years been studied in vitro and in vivo and have scientifically-proven anticancer and chemopreventive effects. These results are not anecdotal anymore. I am not the only myeloma patient to have had success with curcumin (sure, a few haven’t achieved similar results, but that is why we, patients, have to TRY it to see if it works in our particular situation).

My stance is, therefore: what’s the harm in trying a scientifically-proven, non toxic substance for eight weeks to see if your markers improve? If they do, then why not continue taking it? Unless, of course!, you have some health issue such as obstructed bile ducts in the case of curcumin (see my Warnings page).

Okay, so the parenthesis wasn’t "quick" at all!

Let’s have a close look at the Mayo EGCG study. The full study.

According to the Mayo researchers, “EGCG also reduced levels of the protein Mcl-1, an anti-apoptotic protein of known importance in CLL B-cell resistance to apoptosis,” at very very low doses. As usual, I looked up this protein in reference to multiple myeloma, and DUH!, wouldn’t you know it!, the blasted thing turns out to be “essential” for the survival of human myeloma cells in vitro, see abstract: http://tinyurl.com/yuhlku. Essential!

The study provides a detailed description of four CLL cases. Patient number 1 is a 58-year-old woman diagnosed with the “small lymphocytic lymphoma (SLL) variant of CLL/SLL,” whose BMB in 2003, 20 months after diagnosis, showed a “20–25% marrow involvement by CLL/SLL B-cells.” She began taking an OTC (over the counter) green tea supplement containing 315 mg of tea polyphenols. Twice a day. Within a year, “she demonstrated a steady clinical and radiographic decline in her lymphadenopathy with >50% reduction in bilateral axillary nodes and near normalization in the size of all other areas of adenopathy. The patient’s reduction in lymph node size met the NCI criteria for a partial response (PR).” She is doing well (this report was written at 44 months after her diagnosis) and “has not required conventional therapy.”

Patient number 2, a woman, 55 years old, was diagnosed with stage IV disease, asymptomatic. She began drinking a cup of green tea every day ( = two tea bags). Result, 20 months after her initial diagnosis: “>50% decrease in the sum of the products of the six largest lymph node areas consistent with a PR according to the International Working Group criteria for non-Hodgkins lymphoma.”

Patient 3, woman, 50 years old. Five years after being diagnosed with Rai stage 0 CLL (see here for info on CLL staging: http://tinyurl.com/yo2u8m), her absolute lymphocyte count (or ALC) increased, and she developed night sweats and fatigue (that sounds so familiar to me: back in the pre-curcumin era, in 2005, I had both of those symptoms). After reading the Mayo report, she began using a green tea patch, “labeled as containing 300 mg polyphenols,” and drinking three green tea packets a day (300 mg polyphenols per packet). Just one month later her markers had improved. At the time of the report, 77 months after her diagnosis, even though she discontinued the patch and was drinking only one packet of green tea per day, she was classified as stable. No conventional therapy.

The last patient mentioned in the Mayo report is a 60-year-old woman diagnosed with Rai stage 0 CLL in 1995. In 2004 her WBC (white blood count) and ALC increased. This concerned her, so (again, after reading the Mayo in vitro report) she began drinking eight cups of green tea per day. After just one week (ONE WEEK!) her markers had improved. She continued drinking green tea, and her ALC decreased by 50%. 120 months from diagnosis, she “is still asymptomatic from her CLL.”

The discussion part of the study tells us that “In total, our report on these patients with low grade B-cell malignancies adds to the growing evidence that food products that contain polyphenols have anti-tumor activity. In fact, the polyphenol containing agents have not only been shown to have anti-tumor activity but have been linked to chemoprevention of human tumors. A number of epidemiologic studies have linked consumption of green tea to a decreased risk of cancer. A wide range of animal models has also supported green tea’s ability to prevent tumorigenesis. Multiple mechanisms have been proposed as the explanation of the effect of green tea, including anti-angiogenic properties, DNA damage, and inhibition of telomerase. More recent studies of EGCG suggest this agent may affect folate metabolism, suppress transcription factors leading to cell-cycle arrest, and induce oxidative stress through generation of ROS. In vitro studies have also shown EGCG decreases levels of anti-apoptotic proteins at drug levels which are achieved in the serum of tea drinkers in vivo.” Sorry for this tremendously long quote, but there was really no way to summarize or shorten it.

The Mayo report is about CLL patients, of course, but let’s not forget that EGCG has been shown to work against myeloma cells, too. And in fact I am in touch with quite a number of MGUS and SMM folks who take this supplement or drink green tea. Successfully. So now I am more curious than ever to find out how Sherlock and I will do on one gram of EGCG combined with our eight grams of curcumin.

Oh, another important note: the study points out that EGCG should be taken on an empty stomach: “The plasma concentration of free EGCG could be increased five-fold when taken in fasting conditions rather than with food.” If you choose to drink green tea (té verde, in Italian) rather than take an EGCG supplement, by the way, well, in this photo Priscilla, my two-year-old cat, demonstrates how to drink it properly (raise your cup to your mouth…just like this). Sorry, couldn’t resist, she is TOO cute.

The Mayo researchers’ final words, which echo the above-mentioned Italian conference doctor’s thoughts: “These anecdotes cannot determine the effectiveness of tea polyphenols, and highlight the need for clinical trials to define the optimal dosing, schedule, toxicities, and clinical benefits before widespread use can be recommended.” The Mayo EGCG clinical trial is currently recruiting CLL patients, by the way: http://tinyurl.com/2p5l8q.

Well, in my opinion, the Mayo report shows that sometimes we patients just have to jump the gun…proceeding, of course, with well-informed, scientifically-based caution, as always.

Margaret's Corner

Tag: EGCG