Grateloupia longifolia polysaccharide inhibits angiogenesis by downregulating tissue factor expression in HMEC-1 endothelial cells.
1. The antiangiogenic and antitumor properties of Grateloupia longifolia polysaccharide (GLP), a new type of polysaccharide isolated from the marine alga, were investigated with several in vitro and in vivo models. Possible mechanisms underlying its antiangiogenic activity were also assessed. 2. GLP dose-dependently inhibited proliferation of human microvascular endothelial cells (HMEC-1) and human umbilical vein endothelial cells (HUVEC), with IC50 values of 0.86 and 0.64 mg ml(-1), respectively. In tube formation and cell migration assays using HMEC-1 cells, noncytotoxic doses of GLP significantly inhibited formation of intact tube networks and reduced the number of migratory cells. Inhibition by GLP was VEGF-independent. 3. In the chick chorioallantoic membrane (CAM) assay, GLP (2.5 microg egg(-1)) reduced new vessel formation compared with the vehicle control. GLP (0.1 mg plug(-1)) also reduced the vessel density in Matrigel plugs implanted in mice. 4. The levels of pan and phosphorylated receptors for VEGF, VEGFR-1 (flt-1) and VEGFR-2 (KDR) were not significantly altered by 5 mg ml(-1) GLP treatment of HMEC-1, although tissue factor (TF) showed significant decreases at both mRNA and protein levels following GLP treatment. 5. In mice bearing sarcoma-180 cells, intravenous administration of GLP (200 mg kg(-1)) decreased tumor weight by 52% without obvious toxicity. Vascular density in sections of the tumor was reduced by 64% after GLP treatment. 6. Collectively, these results indicate that GLP has antitumor properties, associated at least, in part, with the antiangiogenesis induced by downregulation of TF.
Zhang
Chao
C
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Yang
Fan
F
Zhang
Xiong-Wen
XW
Wang
Shun-Chun
SC
Li
Mei-Hong
MH
Lin
Li-Ping
LP
Ding
Jian
J
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D056890:Eukaryota / Q000737:chemistry*; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011134:Polysaccharides / Q000494:pharmacology*; D012510:Sarcoma 180 / Q000098:blood supply / Q000188:drug therapy; D013925:Thromboplastin / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D020533:Angiogenesis Inhibitors; D011134:Polysaccharides; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D013925:Thromboplastin