Эпигаллокатехин и рак
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- Бұл бет үшін навигация:
- Introduction
- Inhibition of Tumorigenesis in Animal Models and Possible Mechanisms
- Lung tumorigenesis
- Tumorigenesis of digestive tract
- Skin carcinogenesis
- Prostate tumorigenesis and transplanted prostate tumor growth
- Mammary tumorigenesis
Заключительные ЗамечанияВ рассмотренных выше исследованиях на животных продемонстрировали широкую рака профилактических мероприятий чая составляющих в различных органах. Результаты исследований с участием человека, однако, не согласуется. Различий между животным и человеческим исследования может быть связана с тем, что дозы чая используется в исследованиях на животных, как правило, выше, чем те, которые потребляются людьми, и что в условиях эксперимента в исследованиях на животных, как правило, оптимизированы для обнаружения защитный эффект. С другой стороны, результаты эпидемиологических исследований, страдают отсутствием точности измерения количество потребления чая, различные этиологические факторы рака в различных популяциях, индивидуальные различия (например, генетический полиморфизм), образ жизни, связанный с потреблением чая в разных культурах, и другие вмешивающиеся факторы. Более четкие результаты могут быть получены, когда количество потребления чая можно измерить более точно, этиологические факторы более известны и статус курения, употребления алкогольных напитков, и соответствующими генетическим полиморфизмом. Крупных когортных исследований по этой теме необходимы. Хотя результаты эпидемиологических исследований на чай и профилактика рака, не являются окончательными, кофеварка составляющих может по-прежнему использоваться для профилактики рака (лечение precancers) в выбранный орган сайтах, если такая деятельность может быть продемонстрирована в клинических исследования с вмешательством. В этом направлении исследование Betuzzi et al. [90] это очень обнадеживает. Более исследованиях этого типа, а также устные и испытаний средств профилактики рака толстой кишки с хорошо определенными приготовления чая составляющие в достаточном количестве субъектов риску сюда эти раки будут иметь большое значение. IntroductionTea, made from the dried leaves of plant Camellia sinensis, is the second most widely consumed beverage worldwide next to water. Green tea, black tea, and oolong tea are the three major forms of tea. Black tea constitutes 78% of tea produced worldwide; whereas green and oolong tea constitute about 20% and 2%, respectively. Green tea is produced by steaming or pan-frying fresh tea leaves, which inactivates the enzymes and prevents the oxidation of tea constituents. A typical brewed green tea (2g of tea leaves in 200 ml of hot water) contains 500-700 mg of water extractable materials, of which 30-40% (by dry weight) are catechins. (–)-Epigallocatechin-3-gallate (EGCG), (–)-epigallocatechin (EGC), (–)-epicatechin-3-gallate (ECG), and (–)-epicatechin (EC) are the major catechins in tea. Black tea is produced by a process known as fermentation, in which the tea leaves are crushed to promote enzymatic oxidation and subsequent condensation of tea polyphenols, leading to the formation of oligomeric polyphenols (theaflavins) and polymeric polyphenols (thearubigins). Black tea contains 2-6% theaflavins, >20% thearubigins, and 3-10% catechins in the water-extractable materials. Tea leaves also contain 2-5% caffeine in the water-extractable material of green, oolong, and black tea. The possible cancer preventive activity of tea has received much attention in recent years. The inhibitory activities of tea and tea constituents against carcinogenesis at different organ sites have been demonstrated in many animal models. The effect of tea consumption on human cancers, however, remains inconclusive. Mechanisms of action of tea polyphenols, especially EGCG, the most abundant and active catechin, have been extensively investigated. Most of the studies, however, are based on cell culture systems. It is not yet clear which mechanisms are more relevant and important in vivo. This chapter reviews animal studies on the inhibitory effect of tea constituents against tumorigenesis, possible mechanisms of action of tea constituents that may be applicable to human situations, and epidemiological studies on tea and cancer in humans. Results from our own laboratory are discussed in more detail to serve as examples in this field of research.
Administration of green tea, black tea, EGCG, or theaflavins during initiation or promotion stages was shown to significantly decrease (4-methylnitrosamino)-1-(3-pyridyl)-1-butanon (NNK)-induced lung tumorigenesis in rats, mice, or hamsters [9-17]. Treatment with green or black tea for 60 weeks also inhibited the spontaneous formation of lung tumors in A/J mice [18]. Oral administration of green tea infusion reduced the number of lung colonies of mouse Lewis lung carcinoma cells in a metastasis system [19]. These results suggest that tea preparations may be preventive agents for all stages of lung carcinogenesis. Chung et al. [12] showed that the inhibitory effect of caffeine (680 ppm) on NNK-induced lung tumorigenesis in rats was similar to that of 2% black tea (containing 680 ppm caffeine). In a previous study with A/J mice, however, pure EGCG was shown to be slightly more effective than caffeine in inhibiting lung tumorigenesis [10]. Black tea polyphenols have lower bioavailability than green tea polyphenols, and the contribution of caffeine could account for the inhibition of lung tumorigensis by black tea in rats. In our recent study, the oral administration of 0.5% Polyphenon E (PPE, a standardized green tea polyphenol preparation containing 65% EGCG, 25% other catechins, and 0.6% caffeine) or 0.044% caffeine in the drinking fluid for 32 weeks was found to inhibit the progression of lung adenomas to adenocarcinomas in A/J mice that had been treated with a single dose of NNK 20 weeks earlier [17]. Immunohistochemical (IHC) analysis showed that PPE and caffeine treatment inhibited cell proliferation in adenocarcinomas, enhanced apoptosis in adenocarcinomas and adenomas, and decreased levels of c-Jun and phospho-Erk1/2. In the normal lung tissues, neither agent had a significant effect on cell proliferation or apoptosis. Lu et al. [20] recently analyzed the gene expression changes caused by the administration of green tea or PPE to chemically-induced mouse model for lung tumorigenesis. They found that 88 genes that were differentially expressed in tumors (from the normal tissues) were reversed by the treatment and suggested that these genes may be used as markers for tea exposure.
The inhibitory effects of tea and tea polyphenols on intestinal tumorigenesis in mice have been consistently observed in different laboratories [21-24]. We showed that administration of EGCG at 0.02% to 0.32% in drinking fluid dose-dependently inhibited small intestinal tumorigenesis in ApcMin/+ mice, but caffeine did not have such an effect [24]. Western blot analysis indicated that the EGCG administration resulted in increased levels of E-cadherin as well as decreased levels of β-catechin in the nucleus, c-Myc, phospho-Akt, and phospho-Erk in the tumors [24]. In another study with ApcMin/+ mice, PPE (0.12% in diet) was found to decrease intestinal tumor multiplicity by 70.5%, but ECG (0.08% in drinking fluid) had no significant inhibitory effect. [25]. IHC analysis showed that PPE or EGCG treatment increased apoptosis but decreased cell proliferation as well as levels of phospho-Akt and nuclear β-catenin. Green tea administration (0.6% in drinking fluid) inhibited the formation of azoxymethane (AOM)-induced aberrant crypt foci in CF-1 mice on a high-fat diet [26]. EGCG (0.1% in drinking fluid) administration decreased tumor incidence and the number of tumors per tumor-bearing mouse in AOM-treated CF-1 mice [27]. The effects of tea preparation on colon tumorigenesis in rats, however, have not been consistent [28-34]. The lack of a consistent protective effect against colon carcinogenesis is rather surprising because the intestine is considered to be a promising site for chemoprevention with polyphenols that have low systemic bioavailability. EGCG has only limited systemic bioavailability after oral ingestion. Even the absorbed EGCG is excreted mostly into the intestine through the bile. Our recent animal study showed that PPE at 0.24% in the diet significantly inhibited AOM-induced ACF and colon tumor formation in rats by 37% and 55%, respectively (unpublished results).
Conney et al. [35-37] demonstrated inhibitory effects of orally administered tea, decaffeinated tea, and caffeine against UVB-induced skin tumorigenesis in mice and a close association between inhibition of carcinogenesis and reduction of adipose tissue by tea and caffeine [35]. Decaffeinated green tea or decaffeinated black tea was found to be much less effective in inhibiting the tumor formation and reducing fat levels, and adding caffeine to the decaffeinated green or black tea restored the inhibitory effects. When tea polyphenols are administered orally, their low bioavailability in the skin may limit the inhibitory effect; the contribution of caffeine present in tea to inhibiting carcinogenesis could become more important. Topical application of EGCG and caffeine to the skin was shown to decrease, by a similar extent, the incidence, multiplicity, and size of tumors induced by UVB treatment in SKH-1 mice [38, 39]. Prostate tumorigenesis and transplanted prostate tumor growthThere are a total of six studies on the effect of tea on prostate cancer. Four studies were in xenograft models where human prostate cancer cells were inoculated in immune deficient mice, and the tumor growth was inhibited by oral or i.p. administration of tea extracts or polyphenols [40-43]. Gupta et al. [44] reported that oral infusion of the polyphenolic fraction isolated from green tea (0.1% as drinking fluid) significantly inhibited tumor incidence and burden in the prostate as well as metastases to distant sites in an autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model. In a follow-up study [45], the treatment was found to decrease insulin-like growth factor (IGF)-1, phosphor-Akt, and -Erk 1/2 levels, but increase IGF binding protein-3 (IGFBP-3) levels in the prostate cancer of TRAMP mice. Caporali et al. [46] reported similar inhibitory activity of orally administered green tea catechins on prostate tumor formation in the TRAMP model. They showed that levels of clusterin (a protein involved in apoptosis and down-regulated in the prostate during cancer progression) were sustained by the administration [46]. It is not clear whether tea polyphenols inhibit prostate carcinogenesis by a direct action of tea polyphenols that are bioavailable to prostate or by an indirect action such as by affecting androgen metabolism or by affecting circulating serum IGF-1 levels, as observed by Gupta et al. [44].
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