cancer-prevention

Author: Michael N Clifford, Justin JJ van der Hooft, and Alan Crozier

Recent research on the bioavailability of flavan-3-ols after ingestion of green tea by humans is reviewed. Glucuronide, sulfate, and methyl metabolites of (epi)catechin and (epi)gallocatechin glucuronide reach peak nanomolar per liter plasma concentrations 1.6-2.3 h after intake, indicating absorption in the small intestine. The concentrations then decline, and only trace amounts remain 8 h after ingestion. Urinary excretion of metabolites over a 24-h period after green tea consumption corresponded to 28.5% of the ingested (epi)catechin and 11.4% of (epi)gallocatechin, suggesting higher absorption than that of most other flavonoids. The fate of (-)-epicatechin-3-O-gallate, the main flavan-3-ol in green tea, is unclear because it appears unmetabolized in low concentrations in plasma but is not excreted in urine. Possible enterohepatic recirculation of flavan-3-ols is discussed along with the impact of dose and other food components on flavan-3-ol bioavailability. Approximately two-thirds of the ingested flavan-3-ols pass from the small to the large intestine where the action of the microbiota results in their conversion to C-6-C-5 phenylvalerolactones and phenylvaleric acids, which undergo side-chain shortening to produce C-6-C-1 phenolic and aromatic acids that enter the bloodstream and are excreted in urine in amounts equivalent to 36% of flavan-3-ol intake. Some of these colon-derived catabolites may have a role in vivo in the potential protective effects of tea consumption. Although black tea, which contains theaflavins and thearubigins, is widely consumed in the Western world, there is surprisingly little research on the absorption and metabolism of these compounds after ingestion and their potential impact on health.

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Author: Vondina R. Moseley, Jay Morris, Rebecca W. Knackstedt and Michael J. Wargovich

Background: Colon cancer is still the second leading cause of cancer deaths in the United States. Epigenetic gene silencing involving DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) plays an important role in the progression of colon cancer. Materials and Methods: In the present study we found that the sensitivity of colon cancer cells to methylation plays a role in its response to alternative therapy involving the green tea polyphenol, epigallocatechin 3-gallate. HDAC and DNMT protein expression were reduced when methylation-sensitive HCT 116 human colon cancer cells was treated with EGCG, but was relatively stable in the HT-29 cell line. This decrease in expression may be partially explained by our finding that DNMT3A and HDAC3 are degraded in the methylation-sensitive colon cancer cells in part by inhibiting their association with the E3 ubiquitin ligase, UHRF1. Conclusion: These findings provide a rationale for the development of a targeted therapy for methylation-sensitive colon cancer that can include EGCG in combination with other DNMT and HDAC inhibitors.

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(−)-Epigallocatechin-3-gallate, a potential inhibitor to human dicarbonyl/L-xylulose reductase

Author: Xiao-Hui Hu, Li-Ya Ding, Wei-Xue Huang, Xian-Mei Yang, Fang Xie, Min Xu and Long Yu

Dicarbonyl/L-xylulose reductase (DCXR), mainly catalysing the reduction of α-dicarbonyl compounds and L-xylulose, belongs to the short-chain dehydrogenase/reductase superfamily. Its enzyme activity can be inhibited by short-chain fatty acids. In this study, a novel DCXR inhibitor named (−)-epigallocatechin-3-gallate (EGCG) was reported. First, we overexpressed recombinant human DCXR in Escherichia coli, purified the enzyme by affinity chromatography and measured its activity. The inhibition effects of EGCG and its analogues on DCXR were determined subsequently, and EGCG showed the strongest inhibition with 50% inhibition concentration value of 78.8 μM. The surface plasmon resonance analysis also indicated that the equilibrium dissociation constant (K_D) reached to 7.11 × 10−8 M, which implied a high affinity between EGCG and DCXR. From enzyme kinetic analysis, EGCG acted as a mixed inhibitor against its forward and reverse substrates and the coenzyme, reduced nicotinamide adenine dinucleotide phosphate (NADPH). However, the inhibition is pH dependent. The molecular docking finally showed that EGCG formed several hydrogen bonds with the Thr190 residue of DCXR, and the model was further verified by site-directed mutagenesis. Therefore, EGCG is a potential inhibitor to human DCXR.

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Author: Sufang Liu, Hongde Li, Lin Chen, Lifang Yang, Lili Li, Yongguan Tao, Wei Li, Zijian Li, Haidan Liu, Min Tang, Ann M. Bode, Zigang Dong and Ya Cao

Epstein–Barr virus (EBV) reactivation into the lytic cycle plays certain roles in the development of EBV-associated diseases, including nasopharyngeal carcinoma and lymphoma. In this study, we investigated the effects of the tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) on EBV spontaneous lytic infection and the mechanism(s) involved in EBV-positive cells. We found that EGCG could effectively inhibit the constitutive lytic infection of EBV at the DNA, gene transcription and protein levels by decreasing the phosphorylation and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. By using cellular signaling pathway-specific inhibitors, we also explored the signaling mechanisms underlying the inhibitory effects of EGCG on EBV spontaneous lytic infection in cell models. Results show that specific inhibitors of Mitogen-Activated Protein Kinase Kinase (MEK) (PD98059) and phosphatidylinositol 3-kinase [PI3-K (LY294002)] markedly downregulated gene transcription and expression of BZLF1 and BMRF1 indicating that the MEK/ERK1/2 and PI3-K/Akt pathways are involved in the EBV spontaneous lytic cycle cascade. Therefore, one of the mechanisms by which EGCG inhibits EBV spontaneous lytic infection appears to involve the suppression of the activation of MEK/ERK1/2 and PI3-K/Akt signaling.

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Author: Jian-Min Yuan

In contrast to the consistent results of an inhibitory effect of green tea extracts and tea polyphenols on the development and growth of carcinogen-induced tumors in experimental animal models, results from human studies are mixed. Both observational and intervention studies have provided evidence in support of a protective role of green tea intake in the development of oral-digestive tract cancer or an inhibitory role of oral supplementation of green tea extract on a precancerous lesion of oral cavity. Evidence in support of green tea intake against the development of liver cancer risk is limited and inconsistent. An inverse association between green tea intake and lung cancer risk has been observed among never smokers but not among smokers. Although observational studies do not support a beneficial role of tea intake against the development of prostate cancer, several phase 2 clinical trials have shown an inhibitory effect of green tea extract against the progression of prostate premalignant lesions to malignant tumors. Prospective epidemiologic studies so far have not provided evidence for a protective effect of green tea consumption on breast cancer development. Current data neither confirm nor refute a definitive cancer-preventive role of green tea intake. Large randomized intervention trials on the efficacy of green tea polyphenols or extracts are required before a recommendation for green tea consumption for cancer prevention should be made.

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Author: Hannah Gardener, Tatjana Rundek, Clinton B. Wright, Mitchell S. V. Elkind, and Ralph L. Sacco

Coffee and tea are commonly consumed beverages. Inverse associations with mortality have been suggested for coffee and tea, but the relationships with cause-specific mortality are not well understood. We examined regular and decaffeinated coffee and tea in relation to mortality due to all causes, vascular, nonvascular, and cancer in the multi-ethnic, prospective, population-based Northern Manhattan Study. The study population included 2461 participants with diet data who were free of stroke, myocardial infarction, and cancer at baseline (mean age 68.30 ± 10.23 y, 36% men, 19% white, 23% black, 56% Hispanic). During a mean follow-up of 11 y, we examined the associations between coffee and tea consumption, assessed by food frequency questionnaire, and 863 deaths (342 vascular related and 444 nonvascular including 160 cancer deaths) using multivariable-adjusted Cox models. Coffee consumption was inversely associated with all-cause mortality [for each additional cup/d, HR = 0.93 (95% CI: 0.88, 0.99); P = 0.02]. Caffeinated coffee was inversely associated with all-cause mortality, driven by a strong protection among those who drank ≥4 cups/d. An inverse dose-response relationship between tea and all-cause mortality was suggested [for each additional cup/d, HR = 0.91 (95% CI: 0.84, 0.99); P = 0.01]. Coffee consumption ≥4/d was protective against nonvascular death [vs. <1/mo, HR = 0.57 (95% CI: 0.33, 0.97)] and tea consumption ≥2/d was protective against nonvascular death [HR = 0.63 (95% CI: 0.41, 0.95)] and cancer [HR = 0.33 (95% CI: 0.14, 0.80)]. There was a strong inverse association between coffee and vascular-related mortality among Hispanics only. Further study is needed, including investigation into the mechanisms and compounds in coffee and tea responsible for the inverse associations with mortality. The differential relationship between coffee and vascular death across race/ethnicity underscores the need for research in similar multi-ethnic cohorts including Hispanics.

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Author: Gao M, Ma W, Chen XB, Chang ZW, Zhang XD, Zhang MZ

We performed a meta-analysis of the correlation between drinking green tea and the risk of female ovarian tumors. Related literature (2000-2010) was retrieved from PubMed, EMbase, CBMdisc, CNKI, and Wanfang databases. The relationship between the prevalence of ovarian cancer and drinking tea in cohort studies was explored. RevMan5.1.0 software was used for the meta-analysis. A total of 6 case control studies and cohort studies were included. A total of 9113 participants, 3842 cases, and 5271 control cases were included in our analysis. Our analysis indicates that drinking green tea can significantly decrease the risk of ovarian cancer (odds ratio = 0.81; 95% confidence interval = 0.73-0.89; P < .0001). Further research is needed to explore the relationship between drinking green tea and the risk of ovarian tumor in different groups of people and with different tea types and dosages.

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Author: Heidi Fritz, Dugald Seely, Deborah A. Kennedy, Rochelle Fernandes, Kieran Cooley, Dean Fergusson

Background: Green tea is a beverage widely used by lung cancer patients and the public for its purported anticancer properties. The authors conducted a systematic review of green tea for the treatment and prevention of lung cancer. Methodology: Six electronic databases were searched from inception until November 2011 for human interventional and preclinical evidence pertaining to the safety and efficacy of green tea for lung cancer. Results: A total of 84 articles met inclusion criteria: two Phase I trials, three reports of one surrogate study, and 79 preclinical studies. There is a lack of controlled trials investigating green tea for lung cancer. Two Phase I studies showed no objective tumor responses at the maximum tolerated dose, ranging from 3 to 4.2 g/m2 green tea extract (GTE) per day. Four cups of green tea daily decreased DNA damage (8OH-dG) in smokers. Human studies indicate that 800mg of green tea catechins daily does not alter activity of the CYP2D6, CYP1A2, CYP3A4 and CYP2C9 enzymes, however in vitro evidence suggests that green tea may bind to and reduce the effectiveness of bortezomib. Green tea applied topically may improve the healing time of radiation burns. Conclusions: Although some evidence suggests that chemopreventative benefits can be accrued from green tea, there is currently insufficient evidence to support green tea as a treatment or preventative agent for lung cancer. Green tea should not be used by patients on bortezomib therapy. Further research is warranted to explore this natural agent for lung cancer treatment and prevention.

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Author: I-Chun Hou, Saral Amarnani, Mok T Chong, Anupam Bishayee

Gastric cancer (GC) is one of the leading causes of cancer death in the world. Numerous efforts are being made to find chemoprotective agents able to reduce its risk. Amongst these, green tea has been reported to have a protective effect against stomach cancer. This article aims to critically evaluate all epidemiological studies reporting an association between green tea consumption and GC risk. MEDLINE, EBSCOHOST and Google Scholar were used to search for clinical trials of green tea and its correlation to stomach cancer. Studies include cohort and case-control studies. Outcome of interests are inverse association, no association, and positive association. Seventeen epidemiologic studies were reviewed. Eleven studies were conducted in Japan, five in China, and one with Japanese descendent in Hawaii. Ten case-control studies and seven cohort studies were included. The relative risks or odds ratio of GC for the highest level of green tea consumption was compared. Seven studies suggested no association, eight an inverse association, and one a positive association. One study had shown a significantly lowered GC risk when tea was served warm to cold. Another study also showed a significantly risk with lukewarm tea. All studies that analyzed men and women separately have suggested a reduced risk in women than in men, albeit no significant difference. This review demonstrates that there is insufficient information to support green tea consumption reduces the risk of GC. More studies on the subject matter are warranted.

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Author: Naghma Khan, Dhruba J. Bharali, Vaqar M. Adhami, Imtiaz A. Siddiqui, Huadong Cui, Sameh M. Shabana, Shaker A. Mousa and Hasan Mukhtar

In preclinical animal models, several phytochemicals have shown excellent potential to be used as effective agents in preventing and treating many cancers. However, the limited bioavailability of active agents could be one reason for their restricted usefulness for human consumption. To overcome this limitation, we recently introduced the concept of nanochemoprevention by encapsulating useful bioactive food components for their slow and sustained release. Here, we report the synthesis, characterization and efficacy assessment of a nanotechnology-based oral formulation of chitosan nanoparticles encapsulating epigallocatechin-3-gallate (Chit-nanoEGCG) for the treatment of prostate cancer (PCa) in a preclinical setting. Chit-nanoEGCG with a size of <200nm diameter and encapsulating EGCG as determined by dynamic light scattering and transmission electron microscope showed slow release of EGCG in simulated gastric juice acidic pH and faster release in simulated intestinal fluid. The antitumor efficacy of Chit-nanoEGCG was assessed in subcutaneously implanted 22Rν1 tumor xenografts in athymic nude mice. Treatment with Chit-nanoEGCG resulted in significant inhibition of tumor growth and secreted prostate-specific antigen levels compared with EGCG and control groups. In tumor tissues of mice treated with Chit-nanoEGCG, compared with groups treated with EGCG and controls, there was significant (i) induction of poly (ADP-ribose) polymerases cleavage, (ii) increase in the protein expression of Bax with concomitant decrease in Bcl-2, (iii) activation of caspases and (iv) reduction in Ki-67 and proliferating cell nuclear antigen. Through this study, we propose a novel preventive and therapeutic modality for PCa using EGCG that addresses issues related to bioavailability.

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