Hara Office Inc.

Fujieda, Japan

Hara Office Inc.

Fujieda, Japan
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Hara Y.,Hara Office Inc.
Pharmacological Research | Year: 2011

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. © 2011 Elsevier Ltd.


Shimizu M.,Gifu University | Shirakami Y.,Gifu University | Sakai H.,Gifu University | Yasuda Y.,Gifu University | And 5 more authors.
Chemico-Biological Interactions | Year: 2010

(-)-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)-1α, 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 3. h, EGCG caused a decrease in the expression of HIF-1α protein and VEGF, HIF-1α, 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 6. h 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-1α and several major growth factors. EGCG may therefore be useful in the chemoprevention and/or treatment of colorectal cancer. © 2010 Elsevier Ireland Ltd.


Vu H.A.,Waseda University | Beppu Y.,Waseda University | Chi H.T.,Tokyo Medical University | Sasaki K.,Waseda University | And 5 more authors.
Journal of Biomedicine and Biotechnology | Year: 2010

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 100M 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. Copyright © 2010 Hoang Anh Vu et al.


Fu Y.,Georgetown University | Nath R.G.,Georgetown University | Dyba M.,Georgetown University | Cruz I.M.,Georgetown University | And 8 more authors.
Free Radical Biology and Medicine | Year: 2014

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,N6-ethenodeoxyadenosine (DHHedA) in rodent and human tissues by two independent methods: a 32P-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. © 2014 Elsevier Inc.


Vu H.A.,Waseda University | Vu H.A.,University of Medicine and Pharmacy | Beppu Y.,Waseda University | Chi H.T.,Tokyo Medical University | And 7 more authors.
IFMBE Proceedings | Year: 2010

Objectives: Green tea epigalocatechin galate (EGCG) has been shown to exhibit a growth-suppressive effect on human pancreatic cancer cells; however, the exact molecular mechanism by which EGCG suppresses cell proliferation is unclear. We hypothesize that interference with cell adhesion might be one mechanism. Methods: The effect of EGCG on cell adhesion and proliferation was examined using pancreatic cancer cells. Results: 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, when cultured at low density, can be significantly suppressed by EGCG treatment alone in a dose-dependent manner. At a dose of 100 μM that 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. Conclusions: Blocking FAK and IGF-1R by EGCG could prove valuable for targeted therapy, which can use in combination with other therapies, for pancreatic cancer. © Springer-Verlag 2010.


Ly B.T.K.,Tokyo Medical University | Chi H.T.,Tokyo Medical University | Yamagishi M.,Tokyo Medical University | Kano Y.,Tochigi Cancer Center | And 4 more authors.
PLoS ONE | Year: 2013

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. © 2013 Ly et al.


Dash C.,Georgetown University | Chung F.-L.,Georgetown University | Rohan J.A.P.,Georgetown University | Greenspan E.,Georgetown University | And 6 more authors.
BMC Complementary and Alternative Medicine | Year: 2012

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. © 2012 Dash et al.; licensee BioMed Central Ltd.


Shimizu M.,Gifu University | Sakai H.,Gifu University | Shirakami Y.,Gifu University | Yasuda Y.,Gifu University | And 7 more authors.
Cancer Prevention Research | Year: 2011

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-3β (glycogen synthase kinase-3β), 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-1β, 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. ©2011 AACR.


Hara Y.,Hara Office Inc.
Journal of Food and Drug Analysis | Year: 2012

In 1981, we found in collaboration with the late Dr. Tsuneo Kada that the compound in brewed green tea which suppresses the mutability of Bacillus subtilis is(-)-Epigallocatechin gallate(EGCg). Taking advantage of these findings, we started to isolate EGCg and other catechins in large amount from green tea for the first time in the world. We had made use of these samples, for ourselves and for our collaborators around the world, for the elucidation of physiological functions of tea catechins, under the assumption that the various so far claimed health benefits of tea drinking should have derived from tea catechins. From 1996 onward, we have been supplying the defined tea catechin mixture, Polyphenon® E to the US National Cancer Institute(NCI) for their chemoprevention clinical trials in over 20 instances. Separately, we found in 1990 that the topical application of tea catechins on genital warts caused by HPV eliminates the warts in a number of trials in Beijing Cancer Center. The results prompted a German pharmaceutical company to do the Phase 2/3 trials in EU and US. In 2006, the US FDA(Food and Drug Administration) approved the marketing of Polyphenon® E ointment, Veregen®, as the first "Botanical Drug" under FDA regulation. Currently, new developmental work with Theaphenon® E is underway.

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