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1.  Inhibition of FLT3 Expression by Green Tea Catechins in FLT3 Mutated-AML Cells 
PLoS ONE  2013;8(6):e66378.
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a block in differentiation and uncontrolled proliferation. FLT3 is a commonly mutated gene found in AML patients. In clinical trials, the presence of a FLT3-ITD mutation significantly correlates with an increased risk of relapse and dismal overall survival. Therefore, activated FLT3 is a promising molecular target for AML therapies. In this study, we have shown that green tea polyphenols including (−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), and (−)-epicatechin-3-gallate (ECG) suppress the proliferation of AML cells. Interestingly, EGCG, EGC and ECG showed the inhibition of FLT3 expression in cell lines harboring FLT3 mutations. In the THP-1 cells harboring FLT3 wild-type, EGCG showed the suppression of cell proliferation but did not suppress the expression of FLT3 even at the concentration that suppress 100% cell proliferation. Moreover, EGCG-, EGC-and ECG-treated cells showed the suppression of MAPK, AKT and STAT5 phosphorylation. Altogether, we suggest that green tea polyphenols could serve as reagents for treatment or prevention of leukemia harboring FLT3 mutations.
PMCID: PMC3688791  PMID: 23840454
2.  A six-month crossover chemoprevention clinical trial of tea in smokers and non-smokers: methodological issues in a feasibility study 
Chemoprevention crossover trials of tea can be more efficient than parallel designs but the attrition and compliance rates with such trials are unknown.
Attrition (dropouts) and compliance with treatment were assessed in a 25-week randomized, placebo controlled, crossover, feasibility clinical trial of four tea treatments to investigate the effect of tea on oral cancer biomarkers. Each treatment lasted 4 weeks with 2 weeks of washout in between. Participants were 32 smokers and 33 non-smokers without any evidence of premalignant oral lesions. The interventions consisted of packets of green tea, black tea, caffeinated water, or placebo. Participants were assigned to each treatment for four weeks, and were instructed to drink five packets per day while on the treatment. Dropout from the trial and compliance (consumption of ≥ 85% of the prescribed treatment packets) are the main outcome measures reported.
There was a high rate of dropout (51%) from the study, and the rates were significantly higher among smokers (64%) than non-smokers (36%). Among participants who completed the study the rate of compliance was 72%. The highest rates of dropouts occurred between the first and second treatment visits in both smokers (38% dropout) and non-smokers (18% dropout). Throughout the study smokers were more likely to dropout than non-smokers. Black tea treatment was associated with the highest rates of dropout among smokers (37%), but was associated with the lowest rate of dropout among non-smokers (4%).
In a study conducted to test the feasibility of a four-treatment crossover tea trial, a high rate of dropout among smokers and non-smokers was observed. Multi-arm crossover tea trials might pose a higher burden on participants and research is needed to improve adherence and treatment compliance in such trials.
Trial registration number
PMCID: PMC3414766  PMID: 22800470
3.  Green Tea Epigallocatechin Gallate Exhibits Anticancer Effect in Human Pancreatic Carcinoma Cells via the Inhibition of Both Focal Adhesion Kinase and Insulin-Like Growth Factor-I Receptor 
The exact molecular mechanism by which epigallocatechin gallate (EGCG) suppresses human pancreatic cancer cell proliferation is unclear. We show here that EGCG-treated pancreatic cancer cells AsPC-1 and BxPC-3 decrease cell adhesion ability on micro-pattern dots, accompanied by dephosphorylations of both focal adhesion kinase (FAK) and insulin-like growth factor-1 receptor (IGF-1R) whereas retained the activations of mitogen-activated protein kinase and mammalian target of rapamycin. The growth of AsPC-1 and BxPC-3 cells can be significantly suppressed by EGCG treatment alone in a dose-dependent manner. At a dose of 100 μM which completely abolishes activations of FAK and IGF-1R, EGCG suppresses more than 50% of cell proliferation without evidence of apoptosis analyzed by PARP cleavage. Finally, the MEK1/2 inhibitor U0126 enhances growth-suppressive effect of EGCG. Our data suggests that blocking FAK and IGF-1R by EGCG could prove valuable for targeted therapy, which can be used in combination with other therapies, for pancreatic cancer.
PMCID: PMC3034970  PMID: 21318151
4.  A Green Tea Component Suppresses Posttranslational Expression of Basic Fibroblast Growth Factor in Colorectal Cancer 
Gastroenterology  2008;134(7):1972-1980.
Background & Aims
Green tea catechins are known to have anticarcinogenic effects. Epigallocatechin-3-gallate (EGCG) accounts for almost 50% of the total catechin content in green tea extract and has very potent antioxidant effects. EGCG also inhibits angiogenesis, possibly through the inhibition of proangiogenic factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which in turn, inhibits tumor growth and metastasis. However, the exact molecular mechanism by which EGCG suppresses bFGF expression is not known. Our objective was to elucidate the molecular mechanisms by which EGCG inhibits bFGF expression in colorectal cancer.
We examined posttranslational regulation of bFGF by EGCG in human colorectal cancer cells. We also examined bFGF in intestinal tumor formation of APCMin/+ mice with and without catechin treatment.
The bFGF protein was quickly degraded in the presence of EGCG, but a proteasome inhibitor suppressed this degradation. EGCG was also found to increase ubiquitination of bFGF and trypsin-like activity of the 20S proteasome, thereby resulting in the degradation of bFGF protein. Furthermore, EGCG suppressed tumor formation in APCMin/+ mice, compared with vehicle-treated mice, in association with reduced bFGF expression.
The ubiquitin-proteasome degradation pathway contributes significantly to down-regulation of bFGF expression by EGCG. Catechin compounds have fewer adverse effects than chemotherapeutic agents and hence can be used as proof-of-concept in cancer therapeutics to suppress growth and metastasis by targeting proteins such as bFGF.
PMCID: PMC2562743  PMID: 18549879
5.  The β-lactam-resistance modifier (–)-epicatechin gallate alters the architecture of the cell wall of Staphylococcus aureus 
Microbiology (Reading, England)  2007;153(Pt 7):2093-2103.
(–)-Epicatechin gallate (ECg), a component of green tea, sensitizes meticillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics, promotes staphylococcal cell aggregation and increases cell-wall thickness. The potentiation of β-lactam activity against MRSA by ECg was not due to decreased bacterial penicillin-binding protein (PBP) 2a expression or ECg binding to peptidoglycan. A 5-10 % reduction in peptidoglycan cross-linking was observed. Reduced cross-linking was insufficient to compromise the integrity of the cell wall and no evidence of PBP2a activity was detected in the muropeptide composition of ECg-grown cells. ECg increased the quantity of autolysins associated with the cell wall, even though the cells were less susceptible to Triton X-100-induced autolysis than cells grown in the absence of ECg. ECg promoted increased lysostaphin resistance that was not due to alteration of the pentaglycine cross-bridge configuration or inhibition of lysostaphin activity. Rather, decreased lysostaphin susceptibility was associated with structural changes to wall teichoic acid (WTA), an acid-labile component of peptidoglycan. ECg also promoted lipoteichoic acid (LTA) release from the cytoplasmic membrane. It is proposed that ECg reduces β-lactam resistance in MRSA either by binding to PBPs at sites distinct from the penicillin-binding site or by intercalation into the cytoplasmic membrane, displacing LTA from the phospholipid palisade. Thus, ECg-mediated alterations to the physical nature of the bilayer will elicit structural changes to WTA that result in modulation of the cell-surface properties necessary to maintain the β-lactam-resistant phenotype.
PMCID: PMC2063568  PMID: 17600054
6.  Comparative evaluation of antiproliferative, antiangiogenic and apoptosis inducing potential of black tea polyphenols in the hamster buccal pouch carcinogenesis model 
To evaluate the relative chemopreventive efficacy of two black tea polyphenols, Polyphenon-B [P-B] and BTF-35 on 7,12-dimethylbenz [a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis.
Hamsters were divided into 6 groups. The right buccal pouches of animals in groups 1–3 were painted with 0.5% of DMBA three times a week for 14 weeks. While hamsters in group 1 received no further treatment, animals in groups 2 and 3 received diet containing 0.05% P-B and BTF-35 respectively, four weeks before DMBA painting that was continued until the end of the experiments. Animals in groups 4 and 5 were given P-B and BTF-35 alone respectively as in groups 2 and 3. Group 6 animals served as the untreated control. All the animals were sacrificed after 18 weeks. The expression of p21, cyclin D1, glutathione S-transferase pi (GST-P), nuclear factor kappa B (NF-κB), Bcl-2, Bax, cytochrome C, caspase-3, caspase-9, poly(ADP-ribose) polymerase (PARP), cytokeratins and vascular endothelial growth factor (VEGF) was analysed by RT-PCR, immunohistochemical and Western blot analyses.
DMBA treated animals developed buccal pouch carcinomas that displayed increased expression of p21, cyclin D1, GST-P, NF-κB, cytokeratins, VEGF and Bcl-2 with decreased expression of Bax, cytochrome C, caspase-3, caspase-9, and PARP. Dietary administration of both P-B and BTF-35 reduced the incidence of DMBA-induced HBP carcinomas by modulating markers of cell proliferation, cell survival, tumour infiltration, angiogenesis, and apoptosis.
The results of the present study provide a mechanistic basis for the chemopreventive potential of black tea polyphenols. The greater efficacy of BTF-35 in inhibiting HBP carcinogenesis and modulating multiple molecular targets may have a potential role in the prevention of oral cancer.
PMCID: PMC2217513  PMID: 18053169
7.  Potentiation of Catechin Gallate-Mediated Sensitization of Staphylococcus aureus to Oxacillin by Nongalloylated Catechins†  
(−)−Epicatechin gallate (ECg) and (−)−epigallocatechin gallate (EGCg) reduce oxacillin resistance in mecA-containing strains of Staphylococcus aureus. Their binding to staphylococcal cells is enhanced by the nongalloyl analogues (−)−epicatechin (EC) and (−)−epigallocatechin (EGC). EC and EGC significantly increased the capacity of ECg and EGCg to reduce levels of staphylococcal oxacillin resistance.
PMCID: PMC1366925  PMID: 16436737
8.  Efficacy of Polyphenon E, Red Ginseng, and Rapamycin on Benzo(a)pyrene-Induced Lung Tumorigenesis in A/J Mice1 
Neoplasia (New York, N.Y.)  2006;8(1):52-58.
The objective of this investigation was to determine the efficacy of several novel agents in preventing lung tumorigenesis in mice. We evaluated polyphenon E, red ginseng, and rapamycin in A/J mice treated with the tobacco-specific carcinogen benzo(a)pyrene for their ability to inhibit pulmonary adenoma formation and growth. We found that treatment with polyphenon E exhibited a significant reduction on both tumor multiplicity and tumor load (tumor multiplicity x tumor volume) in a dose-dependent fashion. Polyphenon E (2% wt/wt) in the diet reduced tumor multiplicity by 46% and tumor load by 94%. This result provided key evidence in support of a phase II clinical chemoprevention trial of lung cancer. Administration of red ginseng in drinking water decreased tumor multiplicity by 36% and tumor load by 70%. The mammalian target of rapamycin inhibitor rapamycin showed significant efficacy against lung tumor growth in the tumor progression protocol and reduced tumor load by 84%. The results of these investigations demonstrate that polyphenon E, red ginseng, and rapamycin significantly inhibit pulmonary adenoma formation and growth in A/J mice.
PMCID: PMC1584290  PMID: 16533426
Chemoprevention; lung tumor; polyphenon E; red ginseng; rapamycin
9.  Biosynthesized Tea Polyphenols Inactivate Chlamydia trachomatis In Vitro 
Biosynthesized tea polyphenols showed antichlamydial activity against Chlamydia trachomatis D/UW-3/Cx and L2/434/Bu using cell culture. The most active compounds were (−)-epigallocatechin gallate and (−)-epicatechin gallate, followed by (−)-epicatechin (EC). (+)-Epicatechin and (−)-epigallocatechin were intermediate. EC was the least toxic. These results warrant evaluation of tea polyphenols as topical antichlamydial agents.
PMCID: PMC1140499  PMID: 15917555
10.  Exceptionally High Protection of Photocarcinogenesis by Topical Application of (—)-Epigallocatechin-3-Gallate in Hydrophilic Cream in SKH-1 Hairless Mouse Model: Relationship to Inhibition of UVB-Induced Global DNA Hypomethylation1 
Neoplasia (New York, N.Y.)  2003;5(6):555-565.
(—)-Epigallocatechin-3-gallate (EGCG) has been shown to have potent antiphotocarcinogenic activity, but it was required to develop a cream-based formulation for topical application. For topical application, we tested hydrophilic creamas a vehicle forEGCG. Treatment with EGCG (≈ 1 mg/cm2 skin area) in hydrophilic cream resulted in exceptionally high protection against photocarcinogenesis when determined in terms of tumor incidence, tumor multiplicity, and tumor size in a SKH-1 hairless mouse model. EGCG also inhibited malignant transformation of ultraviolet B (UVB)-induced papillomas to carcinomas. In order to determine the mechanism of prevention of photocarcinogenesis, we determined the effect of EGCG on global DNA methylation pattern using monoclonal antibodies against 5-methyl cytosine and DNA methyltransferase in the long-term UV-irradiated skin because altered DNA methylation silencing is recognized as a molecular hallmark of human cancer. We found that treatment with EGCG resulted in significant inhibition of UVB-induced global DNA hypomethylation pattern. Longterm application of EGCG did not show any apparent sign of toxicity inmice when determined in terms of skin appearance, lean mass, total bone mineral content, and total bone mineral density but showed reduction in fat mass when analyzed using dual-energy X-ray absorptiometry. These data suggest that hydrophilic cream could be a suitable vehicle for topical application of EGCG, and that EGCG is a promising candidate for future cancer therapies based on its influence on the epigenetic pathway.
PMCID: PMC1502572  PMID: 14965448
DNA methylation; green tea; skin cancer prevention; (—)-epigallocatechin-3-gallate; ultraviolet radiation
11.  Inhibition of Penicillinase by Epigallocatechin Gallate Resulting in Restoration of Antibacterial Activity of Penicillin against Penicillinase-Producing Staphylococcus aureus 
The combination of epigallocatechin gallate (EGCg, a main constituent of tea catechins) with penicillin showed synergism against 21 clinical isolates of penicillinase-producing Staphylococcus aureus. Besides binding directly to peptidoglycan, the inhibition of penicillinase activity by EGCg is responsible for the synergism. EGCg inhibited the penicillinase activity in a dose-dependent fashion, with a 50% inhibitory concentration of 10 μg/ml.
PMCID: PMC127279  PMID: 12069986
12.  Epigallocatechin Gallate Synergistically Enhances the Activity of Carbapenems against Methicillin-Resistant Staphylococcus aureus 
Combinations of carbapenems and epigallocatechin gallate (EGCg; a main constituent of tea catechins) showed potent synergy against 24 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). MICs of imipenem in the presence of EGCg at 3.125, 6.25, 12.5, and 25 μg/ml, were restored to the susceptible breakpoint (≤4 μg/ml) for 8, 38, 46, and 75% of the MRSA isolates, respectively. Similar results were also observed for combinations of panipenem or meropenem and EGCg. Therefore, the combinations may be worthy of further evaluation in vivo against MRSA infection.
PMCID: PMC127028  PMID: 11796378
13.  Mechanism of Synergy between Epigallocatechin Gallate and β-Lactams against Methicillin-Resistant Staphylococcus aureus 
Compared to MICs (more than 800 μg/ml) of (−)-epigallocatechin gallate (EGCg) against Escherchia coli, MICs of EGCg against methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA) were 100 μg/ml or less. Furthermore, less than 25 μg EGCg per ml obviously reversed the high level resistance of MRSA to all types of tested β-lactams, including benzylpenicillin, oxacillin, methicillin, ampicillin, and cephalexin. EGCg also induced a supersusceptibility to β-lactams in MSSA which does not express mecA, encoding penicillin-binding protein 2′ (PBP2′). The fractional inhibitory concentration (FIC) indices of the tested β-lactams against 25 isolates of MRSA were from 0.126 to 0.625 in combination with 6.25, 12.5 or 25 μg of EGCg per ml. However, no synergism was observed between EGCg and ampicillin against E. coli. EGCg largely reduced the tolerance of MRSA and MSSA to high ionic strength and low osmotic pressure in their external atmosphere, indicating damage of the cell wall. Unlike dextran and lipopolysaccharide, peptidoglycan from S. aureus blocked both the antibacterial activity of EGCg and the synergism between EGCg and oxacillin, suggesting a direct binding of EGCg with peptidoglycan on the cell wall. EGCg showed a synergistic effect with dl-cycloserine (an inhibitor of cell wall synthesis unrelated to PBP2′) but additive or indifferent effect with inhibitors of protein and nuclear acid synthesis. EGCg did not suppress either PBP2′ mRNA expression or PBP2′ production, as confirmed by reverse transcription-PCR and a semiquantitative PBP2′ latex agglutination assay, indicating an irrelevance between the synergy and PBP2′ production. In summary, both EGCg and β-lactams directly or indirectly attack the same site, peptidoglycan on the cell wall. EGCg synergizes the activity of β-lactams against MRSA owing to interference with the integrity of the cell wall through direct binding to peptidoglycan.
PMCID: PMC90539  PMID: 11353619

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