Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 74
Filter
1.
PLoS One ; 17(7): e0271112, 2022.
Article in English | MEDLINE | ID: mdl-35830431

ABSTRACT

The outbreak of the coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 triggered a global pandemic where control is needed through therapeutic and preventive interventions. This study aims to identify natural compounds that could affect the fusion between the viral membrane (receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein) and the human cell receptor angiotensin-converting enzyme 2. Accordingly, we performed the enzyme-linked immunosorbent assay-based screening of 10 phytochemicals that already showed numerous positive effects on human health in several epidemiological studies and clinical trials. Among these phytochemicals, epigallocatechin gallate, a polyphenol and a major component of green tea, could effectively inhibit the interaction between the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein and the human cell receptor angiotensin-converting enzyme 2. Alternately, in silico molecular docking studies of epigallocatechin gallate and angiotensin-converting enzyme 2 indicated a binding score of -7.8 kcal/mol and identified a hydrogen bond between R393 and angiotensin-converting enzyme 2, which is considered as a key interacting residue involved in binding with the severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain, suggesting the possible blocking of interaction between receptor-binding domain and angiotensin-converting enzyme 2. Furthermore, epigallocatechin gallate could attenuate severe acute respiratory syndrome coronavirus 2 infection and replication in Caco-2 cells. These results shed insight into identification and validation of severe acute respiratory syndrome coronavirus 2 entry inhibitors.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 Drug Treatment , COVID-19 , Catechin , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/virology , Caco-2 Cells , Catechin/analogs & derivatives , Catechin/pharmacology , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A/metabolism , Protein Binding , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism
2.
Nutrients ; 13(9)2021 Sep 10.
Article in English | MEDLINE | ID: mdl-34579032

ABSTRACT

Green tea extracts and tea catechins have been shown to prevent or alleviate diabetes. The present study tests the hypothesis that green tea leaves in powder form (GTP), which also contain fiber and other water non-extractable materials, are more effective than the corresponding green tea extracts (GTE) in impeding the development of diabetes in db/db mice. Female db/db mice were treated with a diet containing 1% of GTE, 2% of GTE, 2% of GTP (with the same catechin content as 1% GTE) or 1% GTP. The 1% GTE group had lower food intake, water consumption, body weight and fasting blood glucose levels than the control group, while 2% GTP did not have any significant effect. Dietary 1% GTE also preserved ß-cell insulin secretion. However, 1% GTP increased food intake, water consumption and blood glucose levels. Microbiome analysis with 16S rRNA gene V4 sequencing showed that the gut microbiota was modified by GTE and GTP, and a few bacterial guilds were associated with blood glucose levels. In the Random Forest regression model, the leading predictor of metabolic outcome was food consumption, followed by changes in some bacterial guilds. The results illustrate the importance of food consumption and gut microbiota in affecting the progression of diabetes.


Subject(s)
Diabetes Mellitus/drug therapy , Gastrointestinal Microbiome/drug effects , Plant Extracts/pharmacology , Tea/chemistry , Animals , Blood Glucose , Body Weight , Insulin/blood , Mice , Mice, Inbred NOD , Pancreas/metabolism , Powders
3.
Molecules ; 25(11)2020 Jun 02.
Article in English | MEDLINE | ID: mdl-32498451

ABSTRACT

Most cell-based and animal experiments have shown that green tea catechins (GTC) exhibit various health benefits. In human experimental and epidemiological studies, there are conflicting results, and more precise investigations are required. One of the most effective ways to prove beneficial health effects in humans might be clinical intervention studies. Polyphenon®E was developed as a standardized GTC preparation, which was approved by Food and Drug Administration of US in 2006 as a medication to treat genital warts (Veregen® or sinecatechins). Positive efficacy of Polyphenon®E/sinecatechins/Veregen® (PSV) on anogenital warts has been demonstrated in several epidemiological studies and there have been several case reports to show the clinical effectiveness of PSV. In addition, several studies have provided evidence to suggest that PSV is effective in other human papillomavirus (HPV)-related diseases, although some studies failed to show such effects. Since (-)-epigallocatechin gallate (EGCG) is the major component of PSV, the mechanism of the action of PSV might be deduced from that of EGCG. The microarray analysis of the biopsy samples from the patients suggested that apoptosis induction and the downregulation of inflammation are involved in the mechanism of the action of PSV in the clearance of anogenital warts. Cell-based and animal experiments using PSV also demonstrated effects similar to those elicited by EGCG, explaining how PSV works to induce apoptosis and exert anti-inflammatory actions in HPV-related diseases. Future studies would clarify what kinds of diseases respond effectively to PSV, showing health benefits of GTC and EGCG in humans.


Subject(s)
Catechin/analogs & derivatives , Condylomata Acuminata/drug therapy , Papillomavirus Infections/drug therapy , Alphapapillomavirus/drug effects , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Catechin/pharmacology , Catechin/therapeutic use , Cell Survival/drug effects , Condylomata Acuminata/immunology , Condylomata Acuminata/virology , Gene Expression Regulation/drug effects , Gene Regulatory Networks/drug effects , Humans
4.
Biochem Biophys Res Commun ; 499(3): 681-687, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29608894

ABSTRACT

We searched for inhibitors against prolyl isomerase Pin1 in order to develop functional foods to prevent and cure various Pin1 related diseases such as cancer, diabetes, cardiovascular disease, Alzheimers's disease, and so on. We created a polyphenol library consisting of ingredients in healthy foods and beverages, since polyphenols like epigallocatechin gallate (EGCG) in green tea and 974B in brown algae had been identified as its Pin1 inhibitors. Several polyphenols such as EGCG derivatives, caffeic acid derivatives and tannic acid inhibited Pin1 activity. These results provide a first step in development of the functional foods and beverage targeting Pin1 and its related diseases.


Subject(s)
Food , NIMA-Interacting Peptidylprolyl Isomerase/antagonists & inhibitors , Polyphenols/pharmacology , Caffeic Acids/chemistry , Caffeic Acids/pharmacology , Catechin/chemistry , Catechin/pharmacology , HCT116 Cells , Humans , NIMA-Interacting Peptidylprolyl Isomerase/metabolism , Polyphenols/chemistry , Quercetin/chemistry , Quercetin/pharmacology , Rutin/chemistry , Rutin/pharmacology , Tannins/chemistry , Tannins/pharmacology
5.
J Agric Food Chem ; 65(26): 5365-5374, 2017 Jul 05.
Article in English | MEDLINE | ID: mdl-28595385

ABSTRACT

Data obtained with in vitro fecal incubations and a feeding study indicate black tea theaflavin and its galloyl derivatives are not absorbed in detectable amounts in either the upper or lower gastrointestinal tract. The theaflavin skeleton is comparatively resistant to degradation by colonic bacteria with a 67% recovery being obtained after a 24 h incubation, which yielded 21 phenolic and aromatic catabolites. The theaflavin galloyl moiety was removed by the microbiota, and the released gallic acid further transformed to 3-O- and 4-O-methyl gallic acids, pyrogallol-1-sulfate and pyrogallol-2-sulfate, which were excreted in urine in amounts equivalent to 94% of intake. The main urinary product potentially derived from breakdown of the theaflavin skeleton was 3-(4'-hydroxyphenyl)propionic acid. A number of the colonic catabolites originating from gallic acid and theaflavins has been reported to be bioactive in ex vivo and in vitro models with a variety of potential modes of action.


Subject(s)
Biflavonoids/metabolism , Catechin/metabolism , Colon/metabolism , Tea/metabolism , Adult , Bacteria/isolation & purification , Bacteria/metabolism , Biflavonoids/chemistry , Biological Availability , Camellia sinensis/chemistry , Camellia sinensis/metabolism , Catechin/chemistry , Colon/microbiology , Feces/chemistry , Feces/microbiology , Female , Gastrointestinal Microbiome , Humans , Male , Tea/chemistry
6.
Free Radic Biol Med ; 73: 12-20, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24816294

ABSTRACT

Previous studies showed that 7-(1',2'-dihydroxyheptyl)-substituted etheno DNA adducts are products of reactions with the epoxide of (E)-4-hydroxy-2-nonenal, an oxidation product of ω-6 polyunsaturated fatty acids (PUFAs). In this work, we report the detection of 7-(1',2'-dihydroxyheptyl)-1,N(6)-ethenodeoxyadenosine (DHHedA) in rodent and human tissues by two independent methods: a (32)P-postlabeling/HPLC method and an isotope dilution liquid chromatography-electrospray ionization-tandem mass spectrometry method, demonstrating for the first time that DHHedA is a background DNA lesion in vivo. We showed that DHHedA can be formed upon incubation of arachidonic acid with deoxyadenosine, supporting the notion that ω-6 PUFAs are the endogenous source of DHHedA formation. Because cyclic adducts are derived from the oxidation of PUFAs, we subsequently examined the effects of antioxidants, α-lipoic acid, Polyphenon E, and vitamin E, on the formation of DHHedA and γ-hydroxy-1,N(2)-propanodeoxyguanosine (γ-OHPdG), a widely studied acrolein-derived adduct arising from oxidized PUFAs, in the livers of Long Evans Cinnamon (LEC) rats. LEC rats are afflicted with elevated lipid peroxidation and prone to the development of hepatocellular carcinomas. The results showed that although the survival of LEC rats was increased significantly by α-lipoic acid, none of the antioxidants inhibited the formation of DHHedA, and only Polyphenon E decreased the formation of γ-OHPdG. In contrast, vitamin E caused a significant increase in the formation of both γ-OHPdG and DHHedA in the livers of LEC rats.


Subject(s)
Adenosine/analogs & derivatives , Antioxidants/pharmacology , DNA Adducts/biosynthesis , Deoxyadenosines/biosynthesis , Deoxyguanosine/analogs & derivatives , Adenosine/analysis , Adenosine/biosynthesis , Animals , Antioxidants/chemistry , Arachidonic Acid/chemistry , Catechin/analogs & derivatives , Catechin/pharmacology , Chromatography, Liquid , DNA Adducts/analysis , DNA Adducts/chemistry , Deoxyadenosines/analysis , Deoxyadenosines/chemistry , Deoxyguanosine/biosynthesis , Epoxy Compounds/chemistry , Humans , Liver/metabolism , Rats , Rats, Inbred F344 , Rats, Inbred LEC , Rats, Sprague-Dawley , Spectrometry, Mass, Electrospray Ionization , Thioctic Acid/pharmacology , Vitamin E/pharmacology
7.
PLoS One ; 8(6): e66378, 2013.
Article in English | MEDLINE | ID: mdl-23840454

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Catechin/analogs & derivatives , Leukemia, Myeloid, Acute/drug therapy , fms-Like Tyrosine Kinase 3/genetics , Catechin/pharmacology , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , Down-Regulation/drug effects , Drug Screening Assays, Antitumor , Drug Synergism , Gene Expression/drug effects , Gene Expression Regulation, Leukemic/drug effects , HSP90 Heat-Shock Proteins/metabolism , Humans , Infant , Leukemia, Myeloid, Acute/genetics , Male , Mitogen-Activated Protein Kinases/metabolism , Mutagenesis, Insertional , Phosphorylation , Point Mutation , Protein Processing, Post-Translational , Proto-Oncogene Proteins c-akt/metabolism , STAT5 Transcription Factor/metabolism , Staurosporine/analogs & derivatives , Staurosporine/pharmacology , fms-Like Tyrosine Kinase 3/metabolism
8.
BMC Complement Altern Med ; 12: 96, 2012 Jul 16.
Article in English | MEDLINE | ID: mdl-22800470

ABSTRACT

BACKGROUND: Chemoprevention crossover trials of tea can be more efficient than parallel designs but the attrition and compliance rates with such trials are unknown. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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: ISRCTN70410203.


Subject(s)
Camellia sinensis , Mouth Neoplasms/drug therapy , Patient Compliance/statistics & numerical data , Patient Dropouts/statistics & numerical data , Research Design , Smoking , Tea , Adult , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Biomarkers , Caffeine/pharmacology , Cross-Over Studies , Feasibility Studies , Female , Humans , Male , Middle Aged , Phytotherapy , Plant Preparations/pharmacology , Plant Preparations/therapeutic use , Young Adult
9.
Pharmacol Res ; 64(2): 100-4, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21507345

ABSTRACT

Green tea polyphenols have been reported to have many beneficial health effects. This review describes the development of Polyphenon(®) E as a standardized green tea polyphenol preparation for many clinical trials and as an FDA-approved medication to treat genital warts. The procedures involving this process and the subsequent development of a similar product Theaphenon(®) E are discussed.


Subject(s)
Catechin/administration & dosage , Catechin/chemistry , Tea/chemistry , Condylomata Acuminata/drug therapy , Dietary Supplements , Flavonoids/administration & dosage , Flavonoids/chemistry , Humans , Phenols/administration & dosage , Phenols/chemistry , Polyphenols
10.
Cancer Prev Res (Phila) ; 4(3): 396-403, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21372039

ABSTRACT

Obesity and related metabolic abnormalities, including insulin resistance and a state of chronic inflammation, increase the risk of hepatocellular carcinoma. Abnormal activation of the insulin-like growth factor (IGF)/ IGF-1 receptor (IGF-1R) axis is also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of (-)-epigallocatechin gallate (EGCG), a major biologically active component of green tea, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks and then they received drinking water containing 0.1% EGCG for 34 weeks. At sacrifice, drinking water with EGCG significantly inhibited the development of liver cell adenomas in comparison with the control EGCG-untreated group. EGCG inhibited the phosphorylation of the IGF-1R, ERK (extracellular signal-regulated kinase), Akt, GSK-3ß (glycogen synthase kinase-3ß), Stat3, and JNK (c-Jun NH(2)-terminal kinase) proteins in the livers of experimental mice. The serum levels of insulin, IGF-1, IGF-2, free fatty acid, and TNF-α were all decreased by drinking EGCG, which also decreased the expression of TNF-α, interleukin (IL)-6, IL-1ß, and IL-18 mRNAs in the livers. In addition, EGCG improved liver steatosis and activated the AMP-activated kinase protein in the liver. These findings suggest that EGCG prevents obesity-related liver tumorigenesis by inhibiting the IGF/IGF-1R axis, improving hyperinsulinemia, and attenuating chronic inflammation. EGCG, therefore, may be useful in the chemoprevention of liver tumorigenesis in obese individuals. Cancer Prev Res; 4(3); 396-403. ©2011 AACR.


Subject(s)
Catechin/analogs & derivatives , Diabetes Mellitus, Experimental/complications , Diethylnitrosamine/pharmacology , Liver Neoplasms/chemically induced , Liver Neoplasms/prevention & control , Obesity/complications , Adenoma/metabolism , Animals , Anticarcinogenic Agents/pharmacology , Carcinogens , Catechin/pharmacology , Diabetes Mellitus, Experimental/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Fatty Acids, Nonesterified/metabolism , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Obesity/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptor, IGF Type 1/metabolism
11.
FASEB J ; 24(10): 3882-94, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20522783

ABSTRACT

The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway has been associated with cancer promotion and progression and resistance to treatments in a number of cancers, including prostate adenocarcinoma. Here we provide the first evidence that dietary agents, namely, epigallocatechin gallate (EGCg, IC(50)≈75 µM), resveratrol (IC(50)≈40 µM), or a mixture of polyphenols from green tea [polyphenon E (PPE), IC(50)≈70 µM] or grapevine extract (vineatrol, IC(50)≈30 µM), impede prostate cancer cell growth in vitro and in vivo by inhibiting the SphK1/S1P pathway. We establish that SphK1 is a downstream effector of the ERK/phospholipase D (PLD) pathway, which is inhibited by green tea and wine polyphenols. Enforced expression of SphK1 impaired the ability of green tea and wine polyphenols, as well as pharmacological inhibitors of PLD and ERK activities, to induce apoptosis in PC-3 and C4-2B cells. The therapeutic efficacy of these polyphenols on tumor growth and the SphK1/S1P pathway were confirmed in animals using a heterotopic PC-3 tumor in place model. PC-3/SphK1 cells implanted in animals developed larger tumors and resistance to treatment with polyphenols. Furthermore, using an orthotopic PC-3/GFP model, the chemopreventive effect of an EGCg or PPE diet was associated with SphK1 inhibition, a decrease in primary tumor volume, and occurrence and number of metastases. These results provide the first demonstration that the prosurvival, antiapoptotic SphK1/S1P pathway represents a target of dietary green tea and wine polyphenols in cancer.


Subject(s)
Phosphotransferases (Alcohol Group Acceptor)/physiology , Prostatic Neoplasms/pathology , Tea/chemistry , Wine/analysis , Humans , Male
12.
Chem Biol Interact ; 185(3): 247-52, 2010 May 14.
Article in English | MEDLINE | ID: mdl-20346928

ABSTRACT

(-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, inhibits the growth of colorectal cancer cells by inhibiting the activation of various types of receptor tyrosine kinases (RTKs). The RTK vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis induces tumor angiogenesis in colorectal cancer. This study examined the effects of EGCG on the activity of the VEGF/VEGFR axis and the expression of hypoxia-inducible factor (HIF)-1alpha, which promotes angiogenesis by elevating VEGF levels, in human colorectal cancer cells. Total and phosphorylated (i.e., activated) form (p-VEGFR-2) of VEGFR-2 proteins were overexpressed in a series of human colorectal cancer cell lines. Within 3h, EGCG caused a decrease in the expression of HIF-1alpha protein and VEGF, HIF-1alpha, insulin-like growth factor (IGF)-1, IGF-2, epidermal growth factor (EGF), and heregulin mRNAs in SW837 colorectal cancer cells, which express a constitutively activated VEGF/VEGFR axis. A decrease was also observed in the expression of VEGFR-2, p-VEGFR-2, p-IGF-1 receptor, p-ERK, and p-Akt proteins within 6h after EGCG treatment. Drinking EGCG significantly inhibited the growth of SW837 xenografts in nude mice, and this was associated with the inhibition of the expression and activation of VEGFR-2. The consumption of EGCG also inhibited activation of ERK and Akt, both of which are downstream signaling molecules of the VEGF/VEGFR axis, and reduced the expression of VEGF mRNA in xenografts. These findings suggest that EGCG may exert, at least in part, growth-inhibitory effects on colorectal cancer cells by inhibiting the activation of the VEGF/VEGFR axis through suppressing the expression of HIF-1alpha and several major growth factors. EGCG may therefore be useful in the chemoprevention and/or treatment of colorectal cancer.


Subject(s)
Anticarcinogenic Agents/pharmacology , Catechin/analogs & derivatives , Colorectal Neoplasms/metabolism , ErbB Receptors/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism , Caco-2 Cells , Catechin/pharmacology , Cell Line, Tumor , HCT116 Cells , HT29 Cells , Humans
13.
Pharm Res ; 27(6): 1066-71, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20112129

ABSTRACT

PURPOSE: To compare the chemopreventive efficacy of Polyphenon E (Poly E), (-)-epigallocatechin-3-gallate (EGCG) and Polyphenon E without EGCG (Poly E-EGCG) on the development of benzo(a)pyrene (B(a)P)-induced lung tumors in A/J mice. METHODS: Female A/J mice were given a single intraperitoneal injection of B(a)P (100 mg/kg body weight). One week after B(a)P injection, animals received AIN-76A purified powder diet containing 0.975% (wt/wt) EGCG, 0.525% (wt/wt) Poly E-EGCG or 1.5% (wt/wt) Poly E for 24 weeks or control diet with no additives. RESULTS: Poly E treatment significantly decreased tumor multiplicity by 52% and tumor load by 64%, while EGCG and Poly E-EGCG did not significantly inhibit lung tumor multiplicity. EGCG was more stable in a complex mixture (Poly E) than as a pure compound. CONCLUSION: EGCG was ineffective when administered by diet likely due to its instability. Thus, EGCG's efficacy on mice lung tumorigenesis requires the presence of other tea catechins.


Subject(s)
Anticarcinogenic Agents/therapeutic use , Catechin/analogs & derivatives , Lung Neoplasms/prevention & control , Lung/drug effects , Animals , Catechin/administration & dosage , Catechin/therapeutic use , Chemoprevention , Female , Lung/pathology , Lung Neoplasms/diet therapy , Lung Neoplasms/pathology , Mice
14.
J Biomed Biotechnol ; 2010: 290516, 2010.
Article in English | MEDLINE | ID: mdl-21318151

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Catechin/analogs & derivatives , Focal Adhesion Kinase 1/antagonists & inhibitors , Pancreatic Neoplasms/metabolism , Receptor, IGF Type 1/antagonists & inhibitors , Tea , Antineoplastic Agents/therapeutic use , Antioxidants/metabolism , Antioxidants/pharmacology , Apoptosis/physiology , Catechin/metabolism , Catechin/pharmacology , Catechin/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Humans , Mitogen-Activated Protein Kinases/metabolism , Pancreatic Neoplasms/drug therapy
15.
Fukushima J Med Sci ; 56(1): 17-27, 2010 Jun.
Article in English | MEDLINE | ID: mdl-21485652

ABSTRACT

Although several studies have indicated that (-)-epigallocatechin gallate (EGCG) and lycopene, representative dietary antioxidants, inhibit chemically induced animal tumorigenesis, only a few studies have examined the inhibitory effects of these compounds on spontaneous liver tumorigenesis in rodents. In this study, we investigated the inhibitory effects of these compounds on the formation of spontaneous liver tumors in C3H/HeN mice. We used xeroderma pigmentosum group A (XPA) gene-deficient mice to simultaneously examine whether the knockout mice could be used as a sensitive animal model. Inaddition, we examined the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG)--a marker of reactive oxygen species-induced DNA injury--in liver tissue. Male XPA +/+, XPA +/-, and XPA -/- mice with a C3H/HeN genetic background were divided into 3 groups: control, EGCG, and lycopene. Autopsy at 18 months of age revealed that EGCG and lycopene did not exhibit obvious suppressive effects on the development of liver tumors in any XPA genotype; further, the XPA genotype did not influence any susceptibility to liver tumors. With regard to 8-OHdG levels in non-tumorous liver tissue at 8 months of age, EGCG showed no significant inhibitory effects and lycopene showed significant inhibitory effects only in XPA +/- mice. The present study demonstrates that contrary to previous reports of the inhibitory effects of EGCG and lycopene on the development of various carcinogen-induced animal tumors, these compounds exert no chemopreventive effects on spontaneous liver tumorigenesis in C3H/HeN mice. EGCG and lycopene may inhibit carcinogen-induced tumors through properties other than their antioxidant abilities.


Subject(s)
Anticarcinogenic Agents/pharmacology , Carotenoids/pharmacology , Catechin/analogs & derivatives , Liver Neoplasms, Experimental/prevention & control , Animals , Antioxidants/pharmacology , Catechin/pharmacology , Liver Neoplasms, Experimental/pathology , Lycopene , Male , Mice , Mice, Inbred C3H , Mice, Knockout , Xeroderma Pigmentosum Group A Protein/genetics
16.
Cancer Biol Ther ; 8(20): 1934-9, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19770581

ABSTRACT

Imatinib, a selective tyrosine kinase inhibitor, has been used as a standard first-line therapy for gastrointestinal stromal tumor (GIST) patients. Unfortunately, most patients responding to imatinib will eventually exhibit the resistance, the cause of which is not fully understood. The serious clinical problems of imatinib-resistance demand alternative treatment strategy. (-)-Epigallocatechin-3-gallate (EGCG), a main component of green tea catechin, has been demonstrated potential anti-tumor effects on various types of cancer cells. Here, we report for the first time that EGCG has shown anti-tumor effects on gastrointestinal stromal tumor cell line GIST-T1 by suppressing cell proliferation and eventually inducing cell death via caspase-dependent pathways. GIST-T1 and imatinib resistant GIST-T1 (GIST-T1 IR) cells were used to assess the effects of EGCG. In both cell types, KIT activity was completely inhibited after 4 h treatment with 60 muM EGCG. EGCG specifically inhibited activated KIT, which was demonstrated by using Ba/F3 cells transfected with human wild-type KIT construct. At a dose of 30 muM EGCG, the KIT activity remains but at more than 40 muM EGCG, the KIT activity was abolished in these transfected-Ba/F3 cells. Our results suggest that EGCG has a promising potential as a natural KIT inhibitor and therefore it could be used as a novel therapeutic or preventive reagent for GISTs including the imatinib-resistant cases.


Subject(s)
Apoptosis/drug effects , Caspases/metabolism , Catechin/analogs & derivatives , Piperazines/pharmacology , Proto-Oncogene Proteins c-kit/metabolism , Pyrimidines/pharmacology , Tea/chemistry , Animals , Benzamides , Blotting, Western , Caspase 3/metabolism , Caspase 8/metabolism , Caspase 9/metabolism , Catechin/pharmacology , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Gastrointestinal Stromal Tumors/metabolism , Gastrointestinal Stromal Tumors/pathology , Humans , Imatinib Mesylate , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Time Factors
17.
Chem Biol Interact ; 182(2-3): 159-64, 2009 Dec 10.
Article in English | MEDLINE | ID: mdl-19646978

ABSTRACT

Hepatic fibrosis is a major complication of various chronic liver diseases. Activated hepatic stellate cells (HSCs) play a critical role in the development of liver fibrosis and the axis of platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR), a member of receptor tyrosine kinases (RTKs), is closely associated with the activation of HSC. Insulin-like growth factor (IGF)-1 receptor (IGF-1R), which also belongs to RTKs, interacts with the PDGF/PDGFR axis, thereby cooperatively promoting hepatic fibrosis. We herein examined the effects of (-)-epigallocatechin gallate (EGCG), which inhibits the activation of several types of RTKs, on the development of rat liver fibrosis induced by carbon tetrachloride (CCl4). Drinking water with 0.1% EGCG significantly decreased the serum levels of both aspartate aminotransferase and alanine aminotransferase raised by CCl4, thus indicating an improvement of liver injury. In CCl4-injected rats, EGCG markedly attenuated hepatic fibrosis and decreased the amount of hydroxyproline in the experimental liver. The expression of PDGFRbeta and IGF-1R mRNAs in the liver was significantly lowered by the treatment with EGCG. EGCG also decreased the expression of PDGFRbeta and alpha-smooth muscle actin proteins, thus indicating the inhibition of HSC activation. These findings suggest that EGCG can exert, at least in part, an anti-fibrotic effect on the liver by targeting PDGFRbeta and IGF-1R. EGCG might therefore be useful in both the prevention and treatment of hepatic fibrosis.


Subject(s)
Anticarcinogenic Agents/therapeutic use , Catechin/analogs & derivatives , Liver Cirrhosis/drug therapy , Receptor, IGF Type 1/metabolism , Receptor, Platelet-Derived Growth Factor beta/metabolism , Actins/genetics , Actins/metabolism , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/metabolism , Carbon Tetrachloride , Catechin/therapeutic use , Gene Expression/drug effects , Liver/drug effects , Liver/pathology , Liver Cirrhosis/chemically induced , Male , RNA, Messenger/genetics , Rats , Rats, Wistar , Receptor, IGF Type 1/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics
18.
Cancer Sci ; 100(10): 1957-62, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19558547

ABSTRACT

The receptor tyrosine kinase vascular endothelial growth factor (VEGF) receptor (VEGFR) plays an important role in tumor angiogenesis of hepatocellular carcinoma (HCC). (-)-Epigallocatechin gallate (EGCG), the major biologically active component of green tea, inhibits growth in a variety of human cancer cells by inhibiting the activation of several types of receptor tyrosine kinases. In this study, we examined the effects of EGCG on the activity of the VEGF-VEGFR axis in human HCC cells. The levels of total and phosphorylated (i.e. activated) form of VEGFR-2 protein (p-VEGFR-2) were observed to increase in a series of human HCC cell lines in comparison to the Hc normal human hepatocytes. EGCG preferentially inhibited the growth of HuH7 HCC cells, which express constitutive activation of the VEGF-VEGFR axis, in comparison to Hc cells. Treatment of HuH7 cells with EGCG caused a time- and dose-dependent decrease in the expression of VEGFR-2 and p-VEGFR-2 proteins. The production of VEGF from HuH7 cells was reduced by treatment with EGCG. Drinking of EGCG significantly inhibited the growth of HuH7 xenografts in nude mice and this was associated with inhibition of the activation of VEGFR-2 and its related downstream signaling molecules, including ERK and Akt. EGCG drinking also decreased the expression of Bcl-x(L) protein and VEGF mRNA in the xenografts. These findings suggest that EGCG can exert, at least in part, its growth-inhibitive effect on HCC cells by inhibiting the VEGF-VEGFR axis. EGCG might therefore be useful in the treatment of HCC.


Subject(s)
Anticarcinogenic Agents/pharmacology , Carcinoma, Hepatocellular/metabolism , Catechin/analogs & derivatives , Liver Neoplasms/metabolism , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor Receptor-2/drug effects , Animals , Blotting, Western , Carcinoma, Hepatocellular/genetics , Catechin/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Extracellular Signal-Regulated MAP Kinases/drug effects , Humans , Liver Neoplasms/genetics , Male , Mice , Mice, Nude , Proto-Oncogene Proteins c-akt/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Xenograft Model Antitumor Assays , bcl-X Protein/biosynthesis , bcl-X Protein/drug effects
19.
Biol Pharm Bull ; 32(5): 899-904, 2009 May.
Article in English | MEDLINE | ID: mdl-19420761

ABSTRACT

Migration/invasion is involved in the multiple steps of metastasis, resulting in a poor prognosis of breast cancer. (-)-Epigallocatechin-3-gallate (EGCG) in green tea inhibits the metastasis of some cancer cell lines. Cell migration/invasion assays using Boyden chambers demonstrated that (-)-epigallocatechin (EGC), another green tea catechin, inhibited heregulin-beta1 (HRG)-induced migration/invasion of MCF-7 human breast carcinoma cells to approximately the same extent as EGCG. Assays of cytoskeletal reorganization, Western blotting and immunoprecipitation suggested that EGCG inhibited this migration/invasion by suppressing the HRG-stimulated activation of epidermal growth factor receptor-related protein B2 (ErbB2)/ErbB3/protein kinase B (Akt), whereas EGC did so through pathways including the disruption of the HRG-stimulated activation of ErbB2/ErbB3 but not Akt. EGC, as well as EGCG, could play an important role against the promotion of metastasis of breast cancer cells.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Catechin/analogs & derivatives , Cell Movement/drug effects , Neuregulin-1/pharmacology , Breast Neoplasms/enzymology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Catechin/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Migration Assays , Cell Survival/drug effects , Female , Humans , Neoplasm Invasiveness , Phosphorylation , Protein Multimerization , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-3/antagonists & inhibitors
20.
Cancer Prev Res (Phila) ; 2(6): 531-7, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19470785

ABSTRACT

Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. However, (-)-epigallocatechin-3-gallate (EGCG) alone was shown to be ineffective in preventing lung tumorigenesis in mice by aerosol administration. In this study, Polyphenon E and Polyphenon E without EGCG were administered by aerosol delivery to A/J mice 2 weeks after carcinogen treatment and continuing daily throughout the remainder of the study (20 weeks). An improved aerosol delivery system with a custom-built atomizer, an efficient solvent remove system, and a nose-only exposure chamber was used to provide aerosols with stable size distribution. There were no significant differences in the size distributions of Polyphenon E and Polyphenon E without EGCG. With a relatively low dose level (4.19 mg/kg), Polyphenon E decreased tumor multiplicity by 53%, whereas Polyphenon E without EGCG at the same dose failed to inhibit lung carcinogenesis. These results indicate that aerosol administration can be an effective approach in chemoprevention study, and aerosolized Polyphenon E can significantly inhibit pulmonary adenoma formation and growth in A/J mice. Furthermore, in aerosolized form, EGCG, which is thought to be the most active component of Polyphenon E, has to be present with other tea catechins to show chemopreventive activity on lung tumorigenesis.


Subject(s)
Adenoma/prevention & control , Anticarcinogenic Agents/therapeutic use , Catechin/analogs & derivatives , Lung Neoplasms/prevention & control , Tea/chemistry , Adenoma/chemically induced , Aerosols , Animals , Anticarcinogenic Agents/pharmacology , Antioxidants/pharmacology , Antioxidants/therapeutic use , Benzo(a)pyrene/toxicity , Biological Availability , Catechin/administration & dosage , Catechin/chemistry , Catechin/pharmacology , Catechin/therapeutic use , Drug Screening Assays, Antitumor , Drug Synergism , Female , Lung Neoplasms/chemically induced , Mice , Mice, Inbred A
SELECTION OF CITATIONS
SEARCH DETAIL
...