A prodrug of green tea polyphenol (–)-epigallocatechin-3-gallate (Pro-EGCG) serves as a novel angiogenesis inhibitor in endometrial cancer

• Published in: Cancer letters 2018-01, Vol.412, p.10-20
• Main Authors: Wang, Jianzhang, Man, Gene Chi Wai, Chan, Tak Hang, Kwong, Joseph, Wang, Chi Chiu
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Bioavailability; Cancer; Cancer therapies; Catechin - analogs & derivatives; Catechin - pharmacology; Cell Movement; Chemokine CXCL12 - physiology; CXCL12 protein; Endometrial cancer; Endometrial Neoplasms - drug therapy; Endometrium; Epigallocatechin gallate; Experiments; Female; Gene expression; Green tea; Humans; Hypoxia; Hypoxia inducible factor 1 alpha; Immunoglobulins; Leukocyte migration; Macrophages; Macrophages - physiology; Metastases; Metastasis; Mice; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Pore size; Pro-EGCG; Prodrugs - pharmacology; Prostate; Rodents; Stromal cells; Tea; Tea - chemistry; TOR protein; Tumor cells; Tumor-associated macrophages; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - analysis; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.09.054

Anti-angiogenesis effect of a prodrug of green tea polyphenol (–)-epigallocatechin-3-gallate (Pro-EGCG) in malignant tumors is not well studied. Here, we investigated how the treatment with Pro-EGCG inhibited tumor angiogenesis in endometrial cancer. Tumor xenografts of human endometrial cancer were established and subjected to microarray analysis after Pro-EGCG treatment. First, we showed Pro-EGCG inhibited tumor angiogenesis in xenograft models through down-regulation of vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF1α) in tumor cells and chemokine (C-X-C motif) ligand 12 (CXCL12) in host stroma by immunohistochemical staining. Next, we investigated how HIF1α/VEGFA was down-regulated and how the reduction of CXCL12 inhibited tumor angiogenesis. We found that VEGFA secretion from endometrial cancer cells was decreased by Pro-EGCG treatment through inhibiting PI3K/AKT/mTOR/HIF1α pathway. Furthermore, the down-regulation of CXCL12 in stromal cells by Pro-EGCG treatment restricted migration and differentiation of macrophages thereby inhibited infiltration of VEGFA-expressing tumor-associated macrophages (TAMs). Taken together, we demonstrated that treatment with Pro-EGCG not only decreases cancer cell-secreted VEGFA but also inhibits TAM-secreted VEGFA in endometrial cancer. These findings demonstrate that Pro-EGCG is a novel angiogenesis inhibitor for endometrial cancer. •Pro-EGCG serves as a novel angiogenesis inhibitor in endometrial cancer.•Pro-EGCG reduces cancer cell-secreted VEGFA by inhibiting PI3K/AKT/mTOR/HIF1α pathway.•Pro-EGCG decreases TAM-secreted VEGFA by inhibiting infiltration of TAMs.•Pro-EGCG inhibits CXCL12-induced migration and differentiation of macrophages.