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EGCg Green Tea Extract

67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis
Motofumi Kumazoe1, Kaori Sugihara1, Shuntaro Tsukamoto1, Yuhui Huang1, Yukari Tsurudome1, Takashi Suzuki1, Yumi Suemasu1, Naoki Ueda1, Shuya Yamashita1, Yoonhee Kim1, Koji Yamada1 and Hirofumi Tachibana1,2
1Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, and
2Food Functional Design Research Center, Kyushu University, Fukuoka, Japan.

http://www.jci.org/articles/view/64768

Address correspondence to: Hirofumi Tachibana, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. Phone: [phone]; Fax: [phone]; E-mail: [e-mail].

Published January 25, 2013
Received for publication May 11, 2012, and accepted in revised form November 1, 2012.

The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCδ/acid sphingomyelinase (PKCδ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (–)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.

Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway
Received 26 July 2005; revised 6 March 2006; Accepted 27 March 2006. Available online 21 June 2006.
Abstract
EGCG [(−)epigallocatechin-3-gallate], a green tea-derived polyphenol, has been shown to suppress cancer cell proliferation, and interfere with the several signaling pathways and induce apoptosis. Practically, there is emerging evidence that EGCG has a potential to increase the efficacy of chemotherapy in patients. We hypothesized that EGCG may exert cell cytotoxicity through modulating AMPK (AMP-activated protein kinase) followed by the decrease in COX-2 expression. EGCG treatment to colon cancer cells resulted in a strong activation of AMPK and an inhibition of COX-2 expression. The decreased COX-2 expression as well as prostaglandin E2 secretion by EGCG was completely abolished by inhibiting AMPK by an AMPK inhibitor, Compound C. Also, the activation of AMPK was accompanied with the reduction of VEGF (vascular endothelial growth factor) and glucose transporter, Glut-1 in EGCG-treated cancer cells. These findings support the regulatory role of AMPK in COX-2 expression in EGCG-treated cancer cells. Furthermore, we have found that reactive oxygen species (ROS) is an upstream signal of AMPK, and the combined treatment of EGCG and chemotherapeutic agents, 5-FU or Etoposide, exert a novel therapeutic effect on chemo-resistant colon cancer cells. AMPK, a molecule of newly defined cancer target, was shown to control COX-2 in EGCG-treated colon cancer cells.

Keywords: Epigallocatechin-3-gallate; AMP-activated protein kinase; Cyclooxygenase 2; Etoposide; 5-Flurouracil

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京都大学 再生医科学研究所
緑茶ポリフェノールを利用した新規抗がん剤の開発への期待！
http://www.kyoto-u.ac.jp/ja/news_data/h/h1/news6/2008/081126_1.htm
EGCGは生理的条件下での化学構造安定性が低く、すぐに分解されてしまうことや細胞膜親和性が低いため十分に生理活性が発揮できないなどの問題から、医薬としての応用が限られていました。今回、玄 丞烋（げん しょうきゅう）再生医科学研究所准教授らの研究グループは、リパーゼ（脂肪酸エステルの加水分解酵素）の触媒機能を利用し、EGCGに脂肪酸を導入することで、その化学構造安定性および細胞膜親和性を高める手法を開発しました（図1）。そして、EGCG脂肪酸誘導体を用いて、種々のガン細胞の増殖を抑制したり、担ガンマウスの腫瘍増殖を効果的に阻害することに成功しました。