Green tea polyphenol epigallocatechin-3-gallate inhibits the endothelin axis and downstream signaling pathways in ovarian carcinoma

Abstract

The polyphenol epigallocatechin-3-gallate (EGCG), the principal mediator of the green tea, has been known to possess antitumor effect. The endothelin A receptor (ET A R)/endothelin-1 (ET-1) axis is overexpressed in ovarian carcinoma representing a novel therapeutic target. In this study, we examined the green tea and EGCG effects on two ovarian carcinoma cell lines, HEY and OVCA 433. EGCG inhibited ovarian cancer cell growth and induced apoptosis that was associated with a decrease in Bcl-X L expression and activation of caspase-3. Treatment with green tea or EGCG inhibited ET A R and ET-1 expression and reduced the basal and ET-1-induced cell proliferation and invasion. The EGCG-induced inhibitory effects were associated with a decrease of ET A R-dependent activation of the p42/p44 and p38 mitogen-activated protein kinases and phosphatidylinositol 3-kinase pathway. Remarkably, EGCG treatment resulted in a lowering of basal and ET-1-induced angiogenesis and invasiveness mediators, such as vascular endothelial growth factor and tumor proteinase activation. Finally, in HEY ovarian carcinoma xenografts, tumor growth was significantly inhibited by oral administration of green tea. This effect was associated with a reduction in ET-1, ET A R, and vascular endothelial growth factor expression, microvessel density, and proliferation index. These results provide a novel insight into the mechanism by which EGCG, affecting multiple ET A Rdependent pathways, may inhibit ovarian carcinoma growth, suggesting that EGCG may be useful in preventing and treating ovarian carcinoma in which ET A R activation by ET-1 plays a critical role in tumor growth and progression.

Small Interfering RNA Molecules Targeting Endothelin-Converting Enzyme-1 Inhibit Endothelin-1 Synthesis and the Invasive Phenotype of Ovarian Carcinoma Cells

“…ECE-1 knockdown is therefore a promising approach for inhibiting ET-1 release as well as for inhibiting its actions in endothelial cells. Previously, selective ETA antagonists and green tea extracts were proposed as therapeutic tools in ovarian carcinoma (50,54). ECE-1 siRNA knockdown constitutes another approach able to simultaneously target cancer and endothelial cells, therefore affecting the malignant process and the angiogenesis that accompanies it.…”

Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways

“…Using a slightly different approach, other groups have investigated tea's abilities to prevent tumours by interacting with different signalling pathways in transgenic mice such as Apc min and TRAMP, which develop colon and prostate cancer, respectively [30 -32]. Moreover, tea also possessed an anticarcinogenic activity against the tumour formation induced by the s.c. injection of HEY cells [33], as well as polyphenon B (present in tea) inhibited the carcinogenic activity of DMBA to produce a buccal cancer [34]. Additionally, one of the most important phenolic compounds in tea, epigallocatechin-3-gallate (EGCG), in a different model of transgenic mice for skin cancer, has exhibited a preventive effect and/or improvement of the situation [35,36].…”

Current principles of effective therapy for ovarian cancer

“…Cреди известных противоопухолевых соединений растительного происхождения с мультитаргетной ак-тивностью особого внимания заслуживают пищевые индолы: индол-3-карбинол (I3C), его физиологический метаболит 3,3 , -дииндолилметан (DIM) и флавоноид эпигаллокатехин-3-галлат (EGCG), об этом имеется огромное количество публикаций [11,12,[17][18][19][20][21].…”