A Prodrug of green tea polyphenol (-)-epigallocatechin-3-gallate served as a potentially novel angiogenesis inhibitor in endometrioid endometrial cancer
Refereed conference paper presented and published in conference proceedings

摘要Background and aim: Anti-angiogenesis is a promising treatment in endometrioid endometrial cancer (EEC) while the present anti-angiogenic drugs still have limitations such as drug tolerance, toxicity profıle and substantial costs. (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, is associated with anti-cancer benefıts, but it is unstable and has poor bioavailability. These limitations can be solved through peracetate ester of EGCG as a prodrug (ProEGCG), while little is known about its anti-angiogenesis effect in cancer. The objective is to study the effect and underling mechanism of ProEGCG on EEC angiogenesis. Methods and Results: Tumor xenografts were established by subcutaneous injection of a human EEC cell line (RL95-2) into nude mice, and ProEGCG or control was orally administered every day. 35 days later, mice treated with ProEGCG showed signifıcant reduction in lesion size and MVD without major toxic effects compared to control. To fınd out how ProEGCG inhibits tumor progress and angiogenesis, microarray analysis of excised lesions was conducted and indicated that HIF-1, VEGFA and CXCR4 were downregulated by ProEGCG. Compared to control, immunohistochemistry showed that ProEGCG reduced expression of HIF-1 and VEGFA in RL95-2 cells and decreased CXCR4 expression in tumor-associated macrophages (TAMs) and endothelial cells (ECs). To further study the role of ProEGCG on EEC cells, qRTPCR and Western blotting proved that hypoxia (1% O2) upregulated the level of HIF-1 and VEGFA in EEC cell lines, which was reversed by ProEGCG through inhibiting hypoxia-induced ROS formation. It is known that TAMs play an important role in tumor angiogenesis, and double immunofluorescence of F4/80 and CD206 antibodies in xenografts was applied and found that TAMs infıltration was reduced in ProEGCG group with decreased VEGFA in TAMs. Moreover, proliferation and migration of ECs are critical for tumor angiogenesis. To study the effect of ProEGCG on ECs, tube formation and invasion assays were conducted. The addition of ProEGCG on ECs showed less capillary tube-like structure formation and less invaded ECs by inhibition of CXCR4 expression on ECs. However, it was still unclear if CXCL12, the ligand of CXCR4, was affected. Immunostaining for CXCL12 in tumor lesions indicated that ProEGCG decreased CXCL12 expression in cancer and stromal cells, which was further confırmed in primary human endometrial stromal cells by addition of ProEGCG.

Conclusion: Our study was the fırst to reveal the mechanism of anti-angiogenesis of ProEGCG, which decreased HIF1/VEGFA expression in tumor cells, inhibited recruitment and differentiation of TAMs and tube formation of endothelial cells via CXCL12/CXCR4 reduction. These fındings provided that ProEGCG would be an effective, safe and economic anti-angiogenic drug for EEC.
著者Wang Jianzhang, Man Chi Wai, Yang Xueying, Kwong Joseph, Dou Q. Ping, Chan Tak Hang, Wang Chi Chiu
會議名稱AACR Annual Meeting 2017
會議論文集題名Proceedings of the American Association for Cancer Research
出版社American Association for Cancer Research
頁次41 - 41

上次更新時間 2018-22-01 於 09:22