Antiangiogenic effect of bile acid acylated heparin derivative.
OBJECTIVE
Chemically modified heparin-DOCA was prepared and found to have markedly lower anticoagulant activity than heparin. In the present study, we elucidated the antiangiogenic and antitumoral activities of heparin-DOCA derivative.


METHODS
To evaluate the antiangiogenic and antitumoral effects of heparin-DOCA, capillary-like tube formation assay, Matrigel plug assay in vivo, western blotting for FGFR phosphorylation, ERK and p38 MAPK activities, tumor growth of SCC in vivo and immunostaining of blood vessels in tumor tissues were performed.


RESULTS
Heparin-DOCA inhibited capillary-like tubular structures of endothelial cells and bFGF-induced neovascularizations in Matrigel plug assays. Signaling experiments showed that heparin-DOCA significantly inhibited angiogenesis by suppressing the phosphorylation of FGFR and its downstream signal pathways (ERK and p38 MAPK activities). The antiangiogenic activity of this heparin derivative was found to be closely associated with antitumoral activity in a mouse model. In addition, histological evaluations supported the inhibitory effect of heparin-DOCA on blood vessel formation in tumor tissues.


CONCLUSIONS
Heparin-DOCA derivative exerted a significant antitumoral effect by inhibiting angiogenesis resulting from the disruption of FGF/FGFR and its downstream signal pathways, and could be applied to treat various angiogenic diseases.
Park
Kyeongsoon
K
College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul, 151-742, South Korea.
Kim
Yoo-Shin
YS
Lee
Gee Young
GY
Nam
Ju-Ock
JO
Lee
Seok Ki
SK
Park
Rang-Woon
RW
Kim
Sang Yoon
SY
Kim
In-San
IS
Byun
Youngro
Y
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry* / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D042783:Endothelial Cells; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000032:analysis / Q000378:metabolism; D006493:Heparin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D001647:Bile Acids and Salts; D005346:Fibroblast Growth Factors; D006493:Heparin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases