Antitumor activities of synthetic and natural stilbenes through antiangiogenic action

• Published in: Cancer science Vol. 99; no. 10; pp. 2083 - 2096
• Main Authors: Kimura, Yoshiyuki, Sumiyoshi, Maho, Baba, Kimiye
• Format: Journal Article
• Language: English
• Published: Melbourne, Australia Blackwell Publishing Asia 01.10.2008; Blackwell
• Subjects: Angiogenesis Inhibitors - metabolism; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; Biological and medical sciences; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Colonic Neoplasms - blood supply; Colonic Neoplasms - drug therapy; Culture Media - analysis; Dose-Response Relationship, Drug; Endothelium - drug effects; Endothelium - metabolism; Endothelium, Vascular - cytology; Enzyme Precursors - antagonists & inhibitors; Humans; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Medical sciences; Mice; Mice, Inbred BALB C; Molecular Structure; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Original; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - pharmacology; Tumors; Umbilical Veins - cytology; Vascular Endothelial Growth Factor A - analysis; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Xenograft Model Antitumor Assays; Antineoplastic agent; Cancerology; Synthetic product; Antiangiogenic agent; Biological activity
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/j.1349-7006.2008.00948.x

We reported that the antitumor and antimetastatic actions of resveratrol might be due to the inhibition of tumor‐induced angiogenesis. To search for anticancer agents with stronger activity than resveratrol, we examined the antiangiogenic effects of 21 synthetic and/or natural stilbenes. Among these 21 stilbenes, 2,3‐, 3,4‐, and 4,4′‐dihydroxystilbene inhibited the pro‐matrix metalloproteinase (pro‐MMP)–9 production in colon 26 cells at 5–25 µM, vascular endothelial growth factor (VEGF)–induced human umbilical vein endothelial cell (HUVEC) migration at 10 and 25 µM, and VEGF‐induced angiogenesis at 5–50 µM. Resvertarol inhibited the pro‐MMP‐9 production and VEGF‐induced angiogenesis at 25 or 50 µM. Thus, the inhibition of pro‐MMP‐9 production in colon 26 cells and VEGF‐induced angiogenesis by three dihydroxystilbenes were greater than those of resveratrol. The three dihydroxystilbenes (8 mg/kg, intraperitoneal injection) inhibited the tumor‐induced neovascularization in colon 26–packed chamber‐bearing mice and the tumor growth in colon 26–bearing mice. Furthermore, the three dihydroxystilbenes inhibited VEGF‐induced VEGFR‐2 phosphorylation. On the other hand, the three dihydroxystilbenes had no effect on VEGFR‐1 and‐2 expression, and VEGF‐induced VEGFR‐1 phosphorylation in HUVECs. These findings suggest that the inhibition of tumor‐induced neovascularization by these three dihydroxystilbenes may be due to the inhibition of VEGF‐induced endothelial cell migration and VEGF‐induced angiogenesis through the inhibition of VEGF‐induced VEGFR‐2 phosphorylation in endothelial cells and pro‐MMP‐9 expression in colon 26 cells. (Cancer Sci 2008; 99: 2083–2096)