Oversulfation of fucoidan enhances its anti-angiogenic and antitumor activities.
Fucoidan, a sulfated polysaccharide extracted from brown seaweed, has anticoagulant and antithrombotic activities. Unlike heparin, it shows an inhibitory action on the progression and metastasis of malignant tumors, although the precise mechanisms have not been elucidated. We have demonstrated previously that fucoidan can inhibit tube formation following migration of human umbilical vein endothelial cells (HUVEC) and that its chemical oversulfation enhances the inhibitory potency. In this study, we tested the hypothesis that fucoidan may suppress tumor growth by inhibiting tumor-induced angiogenesis. Both natural and oversulfated fucoidans (NF and OSF) significantly suppressed the mitogenic and chemotactic actions of vascular endothelial growth factor 165 (VEGF(165)) on HUVEC by preventing the binding of VEGF(165) to its cell surface receptor. The suppressive effect of OSF was more potent than that of NF, suggesting an important role for the numbers of sulfate groups in the fucoidan molecule. Consistent with its inhibitory actions on VEGF(165), OSF clearly suppressed the neovascularization induced by Sarcoma 180 cells that had been implanted in mice. The inhibitory action of fucoidan was also observed in the growth of Lewis lung carcinoma and B16 melanoma in mice. These results indicate that the antitumor action of fucoidan is due, at least in part, to its anti-angiogenic potency and that increasing the number of sulfate groups in the fucoidan molecule contributes to the effectiveness of its anti-angiogenic and antitumor activities.
Koyanagi
Satoru
S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Tanigawa
Noboru
N
Nakagawa
Hiroo
H
Soeda
Shinji
S
Shimeno
Hiroshi
H
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008222:Lymphokines / Q000187:drug effects / Q000502:physiology; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013455:Sulfur / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011134:Polysaccharides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013455:Sulfur; C007789:fucoidan; D040301:Vascular Endothelial Growth Factor Receptor-2