- Epigallocatechin gallate (EGCG) from green tea can induce apoptosis in cancerous cells
Diet-based cancer prevention and therapy have received considerable attention in recent years. Green tea, a popular beverage consumed worldwide, has been reported to have inhibitory effects against various types of cancer, such as breast, lung, prostate, and colon cancer.
Most of the chemo-preventive effects of green tea on cancer are attributed to polyphenol compounds, among which epigallocatechin-3-gallate (EGCG) is the most important1. EGCG accounts for 50–80% of the catechin in green tea. There is 200–300 mg of EGCG in a brewed cup (240 mL) of green tea2. By drinking cups of green tea or taking an EGCG tablet, a serum concentration of 0.1–1 μM EGCG can be achieved3,4.
The anti-cancer effect of EGCG has been demonstrated in epidemiological, cell culture, and animal studies, and in clinical trials5. A 10-year prospective study by Nakachi and Imai reported a decreased risk of cancer for those consuming over 10 cups of green tea a day, compared with those consuming below three cups6,7. Recently, Shin et al. found that green tea extract reduced the recurrence rate of colorectal adenomas by 44.2% in a randomized clinical trial in Korea8.
In vitro, EGCG was shown to promote cell growth arrest and induce apoptosis in a variety of human cancer cell lines, including prostate carcinoma cells9,10, epidermoid carcinoma cells11, bladder cancer cells12, and colon cancer cells13. In vivo, oral or intravenous administration of green tea or purified EGCG in mice inhibited angiogenesis and restrained solid tumor growth14,15.
At the molecular level, EGCG has been demonstrated to interact with cancer-related proteins, such as glucose-regulated protein 78 (GRP78)16 and Ras–GTPase-activating protein SH3 domain-binding protein 1 (G3BP1)17, with approximately μΜ affinities.
In EGCG-induced apoptosis and cell growth arrest, p53 was found to play an important role18,19. p53, often referred to as “the guardian of the genome”, is a crucial tumor suppressor mutated in over 50% of human cancer. p53 promotes cell-cycle arrest or apoptosis as a response to cellular stress stimuli, such as oxidative stress, oncogene activation, and DNA damage20,21.
As a transcription factor, p53 is tightly regulated with a short half-life. p53 protein is normally maintained at low levels in healthy mammalian cells by continuous ubiquitylation and subsequent degradation, mediated by murine double minute 2 (MDM2) E3 ligase. Under cellular stress, ubiquitylation of p53 is suppressed and p53 is stabilized. p53 then accumulates in the nucleus and turns on expression of target genes, triggering cell-cycle arrest, apoptosis, and DNA-repair processes20.
Besides acting as a transcription factor, p53 can also translocate to the cytoplasm or mitochondria. p53 interacts directly with anti-apoptotic proteins such as Bax and Bcl2 to induce apoptosis21,22 and is also involved in the anti‑senescent effect of EGCG23,24.
Full length p53 is composed of an N-terminal domain (NTD), a DNA-binding domain (DBD), a tetramerization domain (TET), and a C-terminal regulatory domain (REG) (Fig. 1). The NTD is further divided into two transcriptional activation domains (TAD1 and TAD2) and a proline-rich domain (PRD). NTD is an intrinsically disordered protein (IDP) and interacts with many proteins, acting as a hub for cellular signaling25,26.
NTD is not only required for transactivation, but also binds MDM2 to mediate the ubiquitylation and degradation of p53. Independent of ubiquitylation, MDM2 also inhibits transcription by preventing general transcription factors from binding to NTD27. The apoptosis effect of EGCG on human cancer cells was associated with its interference of MDM2-mediated p53 ubiquitylation28. EGCG is also reported to stabilize p53, with increased phosphorylation on critical serine residues29.
In a recent study, EGCG was identified from a library of 2295 phytochemicals as an inhibitor of p53–MDM2 interaction30. However, the molecular mechanism of how EGCG disrupts MDM2–p53 interaction is not yet understood.
In this work, we demonstrate the direct binding between EGCG and p53, mediated by NTD of p53. We show that the EGCG–p53 interaction disrupts p53 interaction with MDM2 and inhibits ubiquitination of p53, likely stabilizing p53 for anti-tumor activity, providing a structural mechanism for the anti-cancer effect of EGCG.
EGCG–p53 interaction was studied using a sensor chip immobilized with full-length p53 or p53 NTD. As shown in Fig. 1a, b, specific binding of EGCG to full-length p53 and p53 NTD were detected by SPR. The dissociation constant (KD = 4 ± 2 μM) for p53 NTD and EGCG interaction was similar to that (KD = 1.6 ± 1.4 μM) for full-length p53 and EGCG interaction.
The two dissociation constants are within measurement error, indicating that NTD is the major mediator of the p53–EGCG interaction. NTD is also one of the primary binding sites for MDM231, suggesting this EGCG–NTD interaction may impact MDM2-mediated p53 degradation and inhibit NTD interactions with general transcription factors.
Full article: https://www.nature.com/articles/s41467-021-21258-5
- Green Tea May Prevent Alzheimer’s Disease, Say Four New Studies
Could something as simple as drinking green tea protect you from developing Alzheimer’s? A host of new studies have looked at various aspects of how green tea affects the brain, and concluded yes.
Writing in the University of Michigan’s NeuroHealth blog last week, prominent neurologist Henry L. Paulson, MD describes the powerful properties of EGCG (official name: epigallocatechin-3-gallate), a flavonoid in green tea. EGCG, Paulson says, appears to protect the brain from the accumulation of amyloid plaques that scientists believe cause the brain deterioration associated with Alzheimer’s Disease. Paulson describes new research published in the Proceedings of the National Academy of Sciences by Chinese scientist Mi Hee Lim and her team that shows EGCG binds to beta-amyloid, the protein that forms into amyloid plaques, and changes it to prevent that from happening.
In a closely timed and related study published in the Journal of Biological Chemistry, A team of British researchers at the University of Leeds added green tea extract and resveratrol, an extract from red wine (See my recent reporting on resveratrol and weight loss here), to balls of amyloid protein and found that the bioflavonoids prevented the plaques from sticking to nerve cells. All of this research, and more, is described in the June 2013 issue of the Tufts University Health & Nutrition Letter, which appeared in my in-box recently. In a fascinating article titled Green Tea Protects Brain Cells, the editors describe four new studies showing that “green tea may someday be a potent weapon in the fight against Alzheimer’s disease and other forms of dementia.”
To my mind, the most interesting study of those described was published last August in the European Journal of Clinical Nutrition. Unlike most of the current crop of green tea studies, this one was done in humans, albeit just 12 of them. (And it was double blinded and placebo-controlled.) Most importantly, it’s the first study to use MRI technology to actually look at people’s brains to see the effect EGCG might have. Participants were given a beverage to drink after which they performed a memory-stimulating task while researchers monitored their brain function. Two different doses of green tea were tested against a placebo drink that contained no green tea. In those who had received green tea extract, the researchers observed increased activity in the dorsolateral prefontal cortex, which is an area of the brain responsible for processing working memory. They also noted a dose-response, meaning there was an even greater increase in brain activity at the higher dosage of green tea, which backs up the cause and effect relationship.
When it comes to green tea, there really isn’t much of a downside to argue about. No one has ever shown green tea to be harmful to health, and studies have also shown it to be protective against breast cancer and possibly other conditions such as Parkinson’s. I’m guessing the researchers who performed these studies are pouring themselves cups of green tea right now, and I’m about to do the same.
Forbes Magazine, 30.06.2013
- Drinking green tea may help protect against cancer of the digestive system, study says
Green tea may help protect against cancer of the digestive system
THE QUESTION Lab studies have indicated that components of tea could have cancer-fighting capabilities. Might this translate to fewer cases of cancer among those who regularly drink tea, especially green tea?
THIS STUDY analyzed data on 69,310 women, middle-aged and older, who were cancer-free at the start of the study and rarely if ever smoked or drank alcohol. About 28 percent of them drank tea, mostly green tea, three or more times a week. In an 11-year span, 1,255 women developed stomach, esophageal, colorectal, liver, pancreatic or gallbladder/bile duct cancer. Regular tea drinkers were 14 percent less likely to have developed a digestive cancer than were those who never drank tea. Risk fell as tea consumption increased. Those who drank two to three cups of tea daily were 21 percent less likely to have a digestive cancer than non-tea-drinkers. Also, the longer tea-drinking had been a regular habit, the lower the women’s risk, especially for colorectal, stomach and esophageal cancers. Women who had been regular tea-drinkers for 20 years or more were 27 percent less likely to have developed a digestive cancer.
WHO MAY BE AFFECTED? Women who drink tea. Researchers believe the polyphenol compounds in tea, which are antioxidants, are key to its possible effect on cancer. Green tea is thought to be especially beneficial.
CAVEATS The study included only women; whether the finding applies to men remains unclear. Whether tea consumption might affect other types of cancer was not tested. Some of the data came from the women’s responses on questionnaires. All of the women lived in China; whether other aspects of their diet may have affected the results is not known.
FIND THIS STUDY November issue of the American Journal of Clinical Nutrition.
Washington Post, 12.11.2012
- Green tea’s promise of cancer prevention grows
Green tea may be considered a little woo-woo by some mainstream cancer experts but the popular beverage continues to creep toward credibility as a weapon against many forms of the disease. The best studies to date hint that green tea may help ward off cancers of the breast and prostate. And this week oral cancer came one step closer to making the list. Nearly 30,000 Americans will be diagnosed with oral cancer this year, and, with the 5-year survival rate at less than 50%, a little good news is always worth noting.
To get the most oomph out of green tea, most scientists work with a concentrated version called green tea extract (or GTE for short). Like the drink, green tea extract is chock full of polyphenols, plant substances that act as powerful antioxidants in the body. The star player on green tea’s polyphenol team is EGCG (epigallocatechin 2-gallate), a potent slayer of cancer cells.
The new study, appearing in Cancer Prevention Research, suggests that people most at risk of developing oral cancer may benefit from taking green tea extract, especially in higher doses. For the randomized, placebo-controlled trial, researchers at the University of Texas MD Anderson Cancer Center recruited 41 people with pre-cancerous lesions in their mouths. (Heavy use of alcohol and tobacco are the two main risk factors for oral cancers.)
The participants were randomly split into four groups. Three of the groups took green tea extract in various dosages—500 mg, 750 mg, and 1,000 mg—three times a day. The fourth group took a placebo. During the study, the volunteers had two biopsies, one at baseline and one at 12 weeks, to help the scientists figure out whether or not the GTE was working and, if so, how.
At study’s end, nearly 60% of those swallowing the highest doses of GTE—roughly the equivalent of drinking 8 to 10 cups of green tea daily—showed a clinical response, meaning their pre-cancerous lesions looked less menacing, compared to only 18% among those downing placebos. “While still very early, these results certainly encourage more study for patients at highest risk of oral cancer,” says Vassiliki Papadimitrakopoulou, MD, the study’s senior author. “The extract’s lack of toxicity is attractive.”
Time Magazine, 05.11.2009
- Does Green Tea Help the Heart?
The next time you’re offered a choice between Earl Grey and green tea, you might want to go green.
A new study shows that the beverage, which is more popular in Eastern cultures, can protect heart arteries by keeping them flexible and relaxed, and therefore better able to withstand the ups and downs of constant changes in blood pressure. Led by Dr. Nikolaos Alexopoulos of Athens Medical School in Greece, the researchers found that among 14 subjects, those who drank green tea showed greater dilation of their heart arteries on ultrasound 30 min. later than those drinking either diluted caffeine or hot water. That’s because, the scientists speculate, green tea works on the lining of blood vessels, helping cells there to secrete the substances needed to relax the vessels and allow blood to flow more freely. It’s the flavonoids in the tea, which work as antioxidants and help prevent inflammation in body tissue, that keep the vessels pliable. These substances may also protect against the formation of clots, which are the primary cause of heart attacks. “We found very promptly [that] after drinking green tea, there was a protective effect on the endothelium,” says Dr. Charalambos Vlachopoulos, a cardiologist and one of the authors of the study.
All it took, says Vlachopoulos, was 6 g of green tea, which amounts to 3 to 4 cups. To make sure the dilation effect was not due to the small amounts of caffeine found in green tea, the group compared the arterial sizes in the green-tea drinkers with those consuming a diluted caffeine beverage and found no change in arterial size in the caffeine drinkers. Even more intriguing, the beneficial effect seems to be long-lasting and cumulative. When the doctors measured the green-tea drinkers’ arteries two weeks after daily consumption of the beverage, they found that their vessels were more dilated than they had been at the beginning of the study. “It’s something that needs to be investigated, but we think that if someone takes green tea for one or two months, the beneficial effect will be even greater,” says Vlachopoulos.
But experts caution that one study isn’t enough to catapult green tea to wonder-drink status. Dr. Robert Eckel, a professor at the University of Colorado, Denver, and past president of the American Heart Association, notes that endothelial function is affected by a number of factors, including large doses of vitamins E and C. “Green-tea consumption may have beneficial effects on the arteries, but we should stop short of translating that into a recommendation that everybody should be drinking green tea because it’s been proven to reduce heart attacks and strokes,” he says. He acknowledges, however, that early studies hint that green tea may be a good addition to a heart-healthy diet. The American Heart Association does not yet include the beverage in its dietary recommendations, but more studies like this one may change that. In the meantime, if you’re drinking tea, it might not be such a bad idea to go green.
Time Magazine, 03.07.2008
- EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers
Dagmar E Ehrnhoefer, Jan Bieschke, Annett Boeddrich, Martin Herbst, Laura Masino, Rudi Lurz, Sabine Engemann, Annalisa Pastore & Erich E Wanker
The accumulation of ?-sheet–rich amyloid fibrils or aggregates is a complex, multistep process that is associated with cellular toxicity in a number of human protein misfolding disorders, including Parkinson’s and Alzheimer’s diseases. It involves the formation of various transient and intransient, on- and off-pathway aggregate species, whose structure, size and cellular toxicity are largely unclear. Here we demonstrate redirection of amyloid fibril formation through the action of a small molecule, resulting in off-pathway, highly stable oligomers. The polyphenol (- )-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both ?-synuclein and amyloid-? by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of ?-sheet–rich amyloid, the formation of unstructured, nontoxic ?-synuclein and amyloid-? oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.
Max Delbrueck Center for Molecular Medicine (MDC), AG Neuroproteomics, Robert-Roessle-Straße 10, 13092 Berlin, Germany.
National Institute for Medical Research (NIMR), The Ridgeway, Mill Hill, London NW7 1AA, UK.
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.
These authors contributed equally to the work.
Nature Structural & Molecular Biology 15, 558 – 566 (2008)
- Benefit of drinking green tea: The proof is in — drinking tea is healthy, says Harvard Women’s Health Watch
Although tea drinking has been associated with health benefits for centuries, only in recent years have its medicinal properties been investigated scientifically. The October issue of Harvard Women’s Health Watch recognizes the healthy power of tea while helping readers get the most out of their cups.
Tea’s health benefits are largely due to its high content of flavonoids — plant-derived compounds that are antioxidants. Green tea is the best food source of a group called catechins. In test tubes, catechins are more powerful than vitamins C and E in halting oxidative damage to cells and appear to have other disease-fighting properties. Studies have found an association between consuming green tea and a reduced risk for several cancers, including, skin, breast, lung, colon, esophageal, and bladder.
Additional benefits for regular consumers of green and black teas include a reduced risk for heart disease. The antioxidants in green, black, and oolong teas can help block the oxidation of LDL (bad) cholesterol, increase HDL (good) cholesterol and improve artery function. A Chinese study published recently in the Archives of Internal Medicine showed a 46%-65% reduction in hypertension risk in regular consumers of oolong or green tea, compared to non-consumers of tea.
Drinking a cup of tea a few times a day to absorb antioxidants and other healthful plant compounds. In green-tea drinking cultures, the usual amount is three cups per day. Allow tea to steep for three to five minutes to bring out its catechins. The best way to get the catechins and other flavonoids in tea is to drink it freshly brewed. Decaffeinated, bottled ready-to-drink tea preparations, and instant teas have less of these compounds. Tea can impede the absorption of iron from fruits and vegetables. Adding lemon or milk or drinking tea between meals will counteract this problem.
Harvard Health Publications, September 2004