A MMA listserv friend, whose MGUS is stable on a daily intake of epigallocatechin-3-gallate, the green tea polyphenol known more familiarly as EGCG, as well as resveratrol, flaxseed oil capsules and curcumin, recently sent me a few interesting links. Until then, I hadn’t really taken EGCG into consideration. I stand corrected. My more scientifically-minded friend wrote me the following in a recent e-mail: in the case of neoplastic B-cell lymphocyte differentiation into plasma cells, we are looking to curcumin and EGCG not for their anti-oxidant effects, but for their downregulation of NF-kB, which both achieve at different stages of the cell cycle, making them synergistic in this particular cellular scenario. Perfect!

EGCG alone. The first link took me to a study, published in Clinical Cancer Research in 2005, which examined the killing effect of EGCG on MM cells in vitro, and concluded: “Epigallocatechin-3-gallate has potential as a novel therapeutic agent for patients with B-cell malignancies including multiple myeloma via induction of apoptosis mediated by modification of the redox system. In addition, epigallocatechin-3-gallate enhanced As2O3-induced apoptosis in human multiple myeloma cells. See: http://tinyurl.com/22gcme While doing more research on this topic, I came across an abstract co-authored by Kenneth Anderson and published in Blood in 2006. This group of researchers added EGCG to human MM cell lines, inducing apoptosis (programmed death). Healthy cells were spared. They also tested EGCG on mice with tumors grown from MM cells, and observed the same reaction. Conclusion: “These data demonstrate potent and specific anti-myeloma activity of EGCG providing the rationale for its clinical evaluation.” You can read the abstract here: http://tinyurl.com/2d3f9q A University of Wisconsin study published in the March 2007 edition of Clinical Cancer Research shows that EGCG, in combination with other COX-2 inhibitors, blocks COX-2 in prostate cancer, both in vitro and in vivo (mice, again): http://tinyurl.com/2z6ceg

EGCG and curcumin. In 1998, researchers from the Memorial Sloan-Kettering Cancer Center published their findings concerning the effects of EGCG and curcumin on oral cancer. This was the first time the two compounds had been tested together in a cancer study. The researchers discovered that the two substances acted by different mechanisms, and concluded that EGCG and curcumin work synergistically, inhibiting tumor growth in vitro. The abstract and full text are available at: http://tinyurl.com/27ehvt Another study, published in the “Journal of Biological Chemistry” in 2004, also determines that curcumin and EGCG have opposing synergistic effects. It concludes that “The observation that two antioxidants can produce opposite effects is an important consideration in the context of therapeutic antioxidant use.” http://tinyurl.com/2we4ck A 2006 study co-authored by Prof. Aggarwal shows that EGCG and curcumin are also STAT3 inhibitors. See: http://tinyurl.com/2cpwuf (STAT3 is a transcription factor linked to cancer).

Chemopreventive agents. A study titled Using Chemopreventive Agents to Enhance the Efficacy of Cancer Therapy, was published in 2006 in Cancer Research. An important excerpt: “In recent years, more dietary compounds [i.e., genistein, 3,3′ diindolylmethane, indole-3-carbinol (I3C), curcumin, (-)-epigallocatechin- 3-gallate (EGCG), resveratrol, etc.] have been recognized as cancer chemopreventive agents because of their anticarcinogenic activity. Moreover, these compounds also exert the antitumour activities through regulation of different cell signaling pathways. Therefore, common cancer therapies combined with these dietary compounds may exert enhanced antitumor activity through synergic action or compensation of inverse properties. The combination treatment may also decrease the systemic toxicity caused by chemotherapies or radiotherapies because lower doses could be used.” You can read the entire study at: http://tinyurl.com/yv2uyj A 1997 study concerning aerodigestive cancer underscores the importance of looking into chemopreventive substances like EGCG and curcumin which could enhance the effects of chemotherapy: “Chemoprevention of aerodigestive cancer,” by Berwick M.; Schantz S. The main points made by the abstract: “Effective chemoprevention of aerodigestive tumors could have far-reaching effects. [… ] Finally, large-scale trials of the anti-oxidant beta carotene have been disappointing; they have shown that among heavy smokers and possibly heavy alcohol consumers beta carotene increases risk for lung cancer incidence and mortality. These findings underline the critical need to better understand specific mechanisms of action at a particular tissue site, and under various conditions, such as heavy smoking. Novel agents are under development: epigallacatchin gallate, or green tea, curcumin, and a new emphasis on folic acid. Studies to date show that targeting susceptible subgroups, by means of genetic or lifestyle factors, and all ethnic groups will facilitate the goals of chemoprevention studies.” The abstract can be found at: http://tinyurl.com/yv2uyj

EGCG and resveratrol. A March 2007 study, titled “Protein kinase CK2 modulates apoptosis induced by resveratrol and epigallocatechin-3-gallate in prostate cancer cells” shows that both resveratrol and EGCG are chemopreventive agents and should possibly be used in chemotherapy. These researchers examined the effect of both substances on Casein kinase 2 (CK2), which is important in cell proliferation and suppression of apoptosis. By inhibiting the action of this kinase, resveratrol and EGCG were able to induce apoptosis in prostate cancer cells. “Resveratrol and epigallocatechin-3-gallate (EGCG) are important candidates as chemopreventive agents by virtue of their ability to induce apoptosis in cancer cells. [… ] Relatively low doses (10 µmol/L) of resveratrol and EGCG induced a modest proliferative response in cancer cells that could be switched to cell death by moderate inhibition of CK2. These findings characterize, for the first time, the effects of polyphenolic compounds on CK2 signaling in androgen-sensitive and androgen-insensitive prostatic carcinoma cells and suggest that resveratrol and EGCG may mediate their cellular activity, at least in part, via their targeting of CK2. Further, the data hint at the potential of using these polyphenols alongside CK2 inhibitors in combination chemotherapy.” See: http://tinyurl.com/39kkdj

I decided to stop here, but my feeling is that I have barely scratched the surface. There is an overwhelming amount of information on this topic. If anybody finds another study that should be listed here, please let me know. Thank you. I will keep updating this page, as I come across relevant studies.

UPDATE. March 10 2008 post (a bit more info, there). Thanks to Don, 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.” 

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: “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.

October 30 2008 post. One of my July blood tests, the folate, or folic acid, test (I will use the two terms interchangeably), turned out to be quite low. When my family doctor saw that result, he told me that I should probably take a folic acid supplement. I followed his advice for a while. But recently I read some studies that made me stop taking it, while I do more research and ponder the matter.

First things first. Folic acid is a type of the water-soluble B-9 vitamin found the fruit and vegetables we eat–dark green and leafy veggies, nuts and seeds, lightly-cooked beans (folic acid is very susceptible to heat), oranges and grapefruit, etc.

 

Healthy cells need folates, which are essential for cell division…but, and here we get to the crux of the matter, cancer cells do, too. As we know, cancer cells divide and grow very rapidly. For this “divide and prosper quickly” process, they need folates. They gobble ‘em up.

 

Now we will get into some technical stuff. DHFR (=dihydrofolate reductase) is an enzyme that is essential for cancer growth. Some chemotherapy drugs, such as methotrexate, target DHFR. When DHFR is inhibited, you see, cancer cells are not able to use folic acid to keep dividing, which means that tumour growth is slowed down (did I just hear a “wow!”? That was my reaction, too).

 

In sum, as I understand it, no DHFR=no folic acid=slowed tumour growth.

 

There is an obvious consequence, though: DHFR inhibitors can cause folate deficiency. And folate deficiency hinders not only cell division (and DNA synthesis, incidentally), but also the production of red blood cells, which means that folate-deficient folks could develop a sort of anemia called “megaloblastic anemia” (for a lot of info on this particular topic, see: http://www.emedicine.com/med/TOPIC1420.HTM) 

 

So let me get this straight. If I don’t take a folic acid supplement, I risk developing megalobummer anemia. Not good. But if I do take a folic acid supplement, I will be feeding my myeloma cells. Hey, that’s a no-win situation.

 

And now we get to the second part of this post. What does folate deficiency have to do with EGCG?

 

Last week, I happened to come across a 2005 Spanish study (abstract: http://tinyurl.com/5g4o48; full study: http://tinyurl.com/a8crc) showing that people with a folate deficiency should probably not drink a lot of green tea or take too much EGCG in its supplement form. Furthermore, the study linked high levels of green tea consumption to birth defects caused by folic acid deficiency: specifically, spina bifida and anencephaly. Therefore, pregnant women and women even remotely thinking about conceiving should not drink green tea.

 

It seems, in fact, that EGCG behaves like the above-mentioned DHFR inhibitors (except that the green tea extract doesn’t attack healthy cells, only cancerous ones). Yes, it blocks folic acid. And it is precisely its folate-inhibiting activity that makes EGCG so successful in the fight against cancer cell growth. Makes sense, given what we know. But let’s not forget that healthy cells need folates, too. So green tea is good for you only in certain situations, not in others. Caution is the name of the game, as usual.

 

The EGCG-folate issue reminds me of the curcumin-iron “catch-22” situation. Curcumin is an iron chelator (in fact, I am about to read a recent “Blood” study on this very topic, so stay tuned), meaning that it “sucks” iron out of our blood. This is brilliant if you have high serum iron and are at risk of developing cancer. But let’s not forget that the “A” in the myeloma CRAB acronym stands for Anemia. 

 

And here’s the “catch”: anemic curcumin-taking cancer folks who take an iron supplement risk inhibiting the anti-cancer activities of curcumin. So even though my serum iron is low, I have not added an iron supplement to my daily intake. I don’t want to swallow anything that might prevent curcumin from doing its job. For now, I am just trying to obtain a bit of iron from my diet (=red meat once a week, sigh, together with a salad with lots of lemon juice, since vitamin C helps us absorb iron from our food…). I will probably do the same for folic acid. That is, get it from my diet. Period.

 

Anyway, this folate dilemma presents me and perhaps others in my situation (=low folic acid folks) with a tough choice. To take or not to take a folic acid supplement? And how about drinking green tea or taking EGCG capsules?

 

It doesn’t help matters to know that low folic acid intake has been associated with high homocysteine levels, which increase the risk of heart disease and other undesirable conditions.

 

No easy solution, here.

 

February 4 2009 UPDATE: My thanks today go to a blog reader who sent me this link to a February 3 2009 “Blood” abstract: http://tinyurl.com/c9ppr2 Even though I haven’t accessed the full study yet (but hope to do so soon), the abstract provides enough information to determine that if you are on Velcade (bortezomib) or any other boronic acid-based proteasome inhibitor, you shouldn’t even look sideways at a cup of green tea, let alone drink it.

A team of University of Southern California researchers discovered, in fact, that many of the substances contained in green tea, in particular EGCG, effectively prevented tumor cell death induced by bortezomib in vitro and in vivo. In plainer words: when used in the presence of EGCG and other green tea components, Velcade could not kill off any myeloma cells. So today I have a warning: if you are currently taking Velcade, please do not drink any green tea or take any supplements containing EGCG.

Of course, if you are not on bortezomib, well then, that’s another…cup of tea.

P.S. In August 2008, I posted about a “Blood” study on flavonoids and Velcade, please scroll down my Pages to “Dietary flavonoids and Bortezomib” (under “Related Topics”). A curious study, I must say. If you are a CLL patient on Velcade, for instance, you should not take any quercetin. If, however, you are a myeloma patient on Velcade, quercetin can help prime the myeloma cells to the killing effect of this drug. The flavonoid puzzle…

 

June 1 2009 post; update: By now I have a rather daunting backlog of Science Daily updates in my e-box…so, whenever I have a snippet of time, I try to go through a few. As I did yesterday, which is when I came upon a very promising article (http://tinyurl.com/qxcf96) on EGCG, extracted, as we know, from green tea.

 

A recently-published Mayo Clinic trial report tells us that EGCG (capsule form) is well-tolerated by CLL (chronic lymphocytic leukemia) patients, even at high doses….by the way, according to the Mayo researchers, even those who took as many as 2 grams twice a day did not reach the maximum tolerated dose…

 

A few exciting trial results: lymphocyte count was reduced in one-third of participants. Furthermore, The majority of individuals who entered the study with enlarged lymph nodes saw a 50 percent or greater decline in their lymph node size.

 

EGCG is currently being tested on CLL patients in Phase I and II trials. In fact, I just checked the Clinical Trials website and found that the Mayo Clinic study is still recruiting, so if you have CLL, you might be interested in seeing whether you might qualify: http://tinyurl.com/neld9s

 

Well, well. Good stuff. I have been thinking about adding EGCG to my intake (again). Since I have been so busy recently, though, I have been taking only my regular daily dose of curcumin, quercetin and fish oil…a mere 24 capsules a day…ah yes, I think it’s about time to add more capsules to my regimen… 

Ah, here is the link to the study abstract, published in the “Journal of Clinical Oncology” on May 26 2009: http://tinyurl.com/lz3ar5