Green Tea & its Extracts
Stephen B. Strum M.D. 1997

A natural product containing polyphenol compounds that are active against prostate cancer

Introduction

Green tea or a lipid-extract obtained from green tea leaves has multiple pharmacologic actions. Green and black tea are derived from the same plant, Camellia sinensis. However, only green tea is rich in the flavonol group of polyphenols known as catechins. The fermentation process used in making black tea destroys the biologically active polyphenols of the fresh leaf. The catechins as a chemical group have significant free-radical scavenging properties and are potent antioxidants. The four catechins that are found in green tea leaves include:

• Epicatechin (EC)
• Epigallocatechin (EGC)
• Epicatechin gallate (ECG)
• Epigallocatechin-3 gallate (EGCG)
  

Demonstrated biologic activities

EGCG inhibits urokinase

Of these 4 fractions, the gallate catechins, ECG and EGCG, are the most important to the prostate cancer patient. Their pharmacologic activity extends beyond their actions as anti-oxidants and free-radical scavengers. For example, epigallocathechin-3 gallate (EGCG) acts against urokinase, an enzyme often found in large amounts in human cancers. Urokinase breaks down the basement membrane of cell junctions which may be a key step in the process of tumor cell metastasis as well as tumor growth. EGCG attaches to urokinase and prevents these actions.

In a letter to the science journal Nature, Jankun, et.al., from the Medical College of Ohio, reported that EGCG decreased tumor size and could cause complete remission of cancers in mice; this action was mediated by inhibition of urokinase. Black tea, the type most Western residents often drink, does not have this effect because the brewing process destroys the activity of the catechins.

Jankun's group compared the amounts of catechins in green tea to a drug, amiloride, that also acts to inhibit urokinase. Amiloride is a mild diuretic (water pill) usually used to treat high blood pressure and congestive heart failure. "Amiloride is administered in a maximum dose of 20 mg per day, whereas a single cup of tea contains 150 mg of EGCG, and some tea lovers consume up to 10 cups a day," they wrote. "Such high levels of a urokinase inhibitor are likely to have a physiological effect and could reduce incidence of cancer in humans or the size of cancers already formed." (Jankun J, Selman SH, et al. Why drinking green tea could prevent cancer. Nature 1997 Jun 5;387(6633):561).

Green tea polyphenols(GTP) inhibits ornithine decarboxylase

In vivo studies with skin carcinoma demonstrated that GTP inhibits ornithine decarboxylase (ODC). ODC is the rate-limiting enzyme in the pathway of mammalian polyamine biosynthesis. Polyamines affect DNA, RNA and protein synthesis. For these reasons, ODC activity is said to be closely associated with tumor promotion. GTP inhibit ODC resulting in a decrease in polyamine synthesis and cell growth.

Carlin, et.al., evaluated the effect of GTP on the growth of prostate cancer cells in laboratory experiments and measured its effect on ODC activity. In this study, CWR-22 prostate cancer xenografts were harvested from nude mice. A cell suspension was plated in soft agar at a concentration of 0.05 million cells/ml with 25 nM testosterone and varying concentrations of GTP. A dose-dependent inhibition of growth by GTP was observed:

GTP Dose mcg/ml	0	10	20	30	40	80	160	320
Colonies number	499	491	470	445	331	290	265	250

The authors also studied the effect of testosterone on ODC activity. Testosterone induced an increase in ODC activity. Minced CWR-22 xenograft was then treated with varying concentrations of GTP and then with 25 nM testosterone. ODC activity was determined. The addition of GTP resulted in a dose dependent decrease in ODC activity.

GTP Dose mcg/ml	0	20	40	60
ODC Activity	1250	950	800	500

(Carlin BI, Pretlow TG, Pretlow TP et al. Green tea polyphenols inhibit growth of prostate cancer xenograft cwr-22 and decrease ornithine decarboxylase activity: implications for prostate cancer chemoprevention. J Urol 155(5):510A, 1996)

ECG and EGCG inhibits 5-alpha reductase (5AR)

Inhibitors of 5AR may be effective in the treatment of 5 alpha dihydrotestosterone-dependent abnormalities, such as benign prostate hyperplasia, prostate cancer, and certain skin diseases. The green tea catechins are potent inhibitors of type 1 but not type 2 5AR; they also inhibit accessory sex gland growth in the rat. These results suggest the certain tea gallates can regulate androgen action in target organs. (Liao S, Hipakka, RA. Selective inhibition of steroid 5a -reductase [5AR] by tea epicatechin-3-gallate and epigallocatechin-3-gallate. Biochemical and Biophysical Research Communications; 214(3), 833-838,1995).

Green Tea EGCG inhibits growth and induces regression of human prostate and breast cancers in athymic mice

Long-term consumption of tea catechins has been shown to have anti-tumor effects in animals. The same tea catechins are consumed commonly in China and Japan possibly explaining why the mortality of prostate cancer and breast cancer is lower in Asian countries than in Western countries. In this study the authors investigated the effect of intra-peritoneal injections of different catechins on the growth of human prostate cancer cell lines PC-3 and LnCaP and the human breast cancer cell line MCF-7 grown in nude mice.

As shown in the figure below, the injection of EGCG slowed the growth of tumor when administered to the control mice on day 14 while the growth of tumor accelerated when EGCG was stopped in the PC-3 line on day 14. Inhibition of PC-3 growth was EGCG specific; it was not seen with EC, EGC or ECG. The galloyl group of EGCG appears to be necessary for tumor growth inhibition since EGC is not active. EGCG accounts for ~ 50% of the solid matter in the hot water extract of green tea consumed as a beverage.

The frequency of the latent, localized type of prostate cancer does not vary significantly between Eastern and Western cultures, but the clinical incidence of metastatic prostate cancer is generally low in Japan and other Asian countries in contrast to the common occurrence of metastatic disease in Europe and the United States. One possible explanation is that EGCG in consumed green tea in Asian countries prevents the progression and metastasis of prostate cancer cells. (Liao S, Umekita Y, Guo J et al. Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Letters 96:239-243, 1995).

Green tea and EGCG inhibits oncogene expression

In another laboratory experiment, carcinogens were used to induce oncogene expression in two mouse models involving lung oncogenes and skin oncogenes. In the mouse lung oncogene experiment, control mice were evaluated versus mice given 2% green tea in drinking water. The controls showed high levels of lung oncogene expression involving oncogenes c-myc, c-raf and c-H-ras. Green tea inhibited oncogene expression at rates of 50%, 20% and 50%, respectively. In the mouse skin oncogene experiment, control mice were evaluated versus mice given topical EGCG. The control mice showed high levels of skin oncogene expression involving the ornithine decarboxylase gene, protein kinase C and c-myc oncogene. EGCG inhibited all of the above oncogenes in a dose-dependent fashion. (Hu G, and Chen J. Inhibition of oncogene expression by green tea and epigallocatechin gallate in mice. Nutrition and Cancer 24(2): 203-209, 1995).

Prostate Cancer Research Institute (PCRI)

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