(–)‐Epigallocatechin gallate suppresses the growth of human hepatocellular carcinoma cells by inhibiting activation of the vascular endothelial growth factor–vascular endothelial growth factor receptor axis

Shirakami, Yohei; Shimizu, Masahito; Adachi, Seiji; Sakai, Hidetaka; Nakagawa, Takayuki; Yasuda, Yoshitaka; Tsurumi, Hisashi; Hara, Yukihiko; Moriwaki, Hisataka

doi:10.1111/j.1349-7006.2009.01241.x

Cited by 90 publications

(77 citation statements)

References 41 publications

(76 reference statements)

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“…HepG2, SMMC7721 and SK-hep1 are classic cell lines for studying HCC. Studies have shown that EGCG induced tumor apoptosis, and prevented tumor invasion and metastasis (6,8,(15)(16)(17). We therefore, used these cell lines to investigate the effect of EGCG on inhibition of cell growth and the underlying mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…the thrombin-PAR1/PAR4-p42/p44 MAPKinase invasive signaling axis in hepatocellular carcinoma cells (30). HIF-1α/ VEGF function was also a therapeutic target for EGCG in cancer chemoprevention and anticancer therapy (15,22). EGCG also delayed HCC cell growth through inhibition of Bcl-2 family (16,19) or induced apoptosis in HCC cells via downregulation of COX-2 and Bcl-2, and consequently activated caspase-9 and caspase-3 (31).…”

Section: Discussionmentioning

confidence: 99%

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Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

Shen

Zhang

Yan

et al. 2014

International Journal of Oncology

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Abstract. Epigallocatechin-3-gallate (EGCG) has been shown to inhibit the growth and induce apoptosis of certain cancer cells. The aim of this study was to determine the role of EGCG in hepatocellular carcinoma (HCC) and the underlying mechanism(s) thereof. MTT assay was used to determine the cell growth inhibition by EGCG. Apoptosis induced by EGCG was investigated by both AO/EB staining and flow cytometry. The cell cycle distribution was analyzed by flow cytometry. The mRNA levels of the AKT pathway were analyzed by quantitative PCR. The expression of AKT and its phosphorylation at Ser473 were detected by western blotting. The IC 50 of EGCG at 48 h for HepG2, SMMC7721 and SK-hep1 cells were 74.7, 59.6 and 61.3 µg/ml, respectively. Significantly higher proportion of SMMC7721 cells entered the S phase upon treatment with EGCG for 48 h compared with control cells. EGCG decreased the mRNA levels of PI3K, AKT and NF-κB. The protein levels of AKT decreased and its phosphorylation at Ser473 was downregulated with EGCG treatment. EGCG inhibited growth by affecting the cell cycle and induced apoptosis in different HCC cells by downregulating PI3K/ AKT activity. The results suggest the potential of EGCG as an anticancer agent in the prevention or treatment of HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

Shen

Zhang

Yan

et al. 2014

International Journal of Oncology

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“…EGCG exerts an inhibitory effect in many cancers, such as prostate cancer [20,21] and liver cancer [22] . Previous studies have shown that EGCG decreased the expression of COX-2 [23] and mPGES [15] .…”

Section: Discussionmentioning

confidence: 99%

Prostanoid EP1 receptor as the target of (−)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro

et al. 2012

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Aim: To investigate the effects of (-)-epigallocatechin-3-gallate (EGCG), an active compound in green tea, on prostaglandin E 2 (PGE 2 )-induced proliferation and migration, and the expression of prostanoid EP 1 receptors in hepatocellular carcinoma (HCC) cells. Methods: HCC cell line HepG2, human hepatoma cell lines MHCC-97L, MHCC-97H and human hepatocyte cell line L02 were used. Cell viability was analyzed using MTT assay. PGE 2 production was determined with immunoassay. Wound healing assay and transwell filter assay were employed to assess the extent of HCC cell migration. The expression of EP 1 receptor and Gq protein were examined using Western blot assay. Results: PGE 2 (4-40000 nmol/L) or the EP 1 receptor agonist ONO-DI-004 (400-4000 nmol/L) increased the viability and migration of HepG2 cells in concentration-dependent manners. EGCG (100 μg/mL) significantly inhibited the viability and migration of HepG2 cells induced by PGE 2 or ONO-DI-004. HepG2 cells secreted an abundant amount of PGE 2 into the medium, and EGCG (100 μg/mL) significantly inhibited the PGE 2 production and EP 1 receptor expression in HepG2 cells. EGCG (100 μg/mL) also inhibited the viability of MHCC-97L cells, but not that of MHCC-97H cells. Both EGCG (100 μg/mL) and EP 1 receptor antagonist ONO-8711 inhibited PGE 2 4 μmol/L and ONO-DI-004 400 nmol/L-induced growth and migration of HepG2 cells. Both EGCG (100 μg/mL) and ONO-8711 210 nmol/L inhibited PGE 2 -and ONO-DI-004-induced EP 1 expression. EGCG and ONO-8711 had synergistic effects in inhibiting EP 1 receptor expression. PGE 2 , ONO-DI-004, ONO-8711, and EGCG had no effects on Gq expression in HepG2 cells, respectively. Conclusion: These findings suggest that the anti-HCC effects of EGCG might be mediated, at least partially, through the suppressing EP 1 receptor expression and PGE 2 production.

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“…The mice in group 3 were given 0.1% EGCG throughout the experiment. The concentration of EGCG (0.1%), which was established according to the findings of previous chemopreventive studies (16,23), was within the physiologic range after daily intake of GTCs in human per unit body weight basis (24). The mice in groups 1 and 4 were given tap water without EGCG.…”

Section: Methodsmentioning

confidence: 99%

Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-db/db Mice

Shimizu

Sakai²,

Shirakami³

et al. 2011

Cancer Prevention Research

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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 (À)-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-3b (glycogen synthase kinase-3b), 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-a were all decreased by drinking EGCG, which also decreased the expression of TNF-a, interleukin (IL)-6, IL-1b, 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. Ó2011 AACR.

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(–)‐Epigallocatechin gallate suppresses the growth of human hepatocellular carcinoma cells by inhibiting activation of the vascular endothelial growth factor–vascular endothelial growth factor receptor axis

Cited by 90 publications

References 41 publications

Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway

Prostanoid EP1 receptor as the target of (−)-epigallocatechin-3-gallate in suppressing hepatocellular carcinoma cells in vitro

Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-db/db Mice

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