Oligomannurarate sulfate, a novel heparanase inhibitor simultaneously targeting basic fibroblast growth factor, combats tumor angiogenesis and metastasis.

Abstract

Inhibitors of tumor angiogenesis and metastasis are increasingly emerging as promising agents for cancer therapy. Recently, heparanase inhibitors have offered a new avenue for such work because heparanase is thought to be critically involved in the metastatic and angiogenic potentials of tumor cells. Here, we report that oligomannurarate sulfate (JG3), a novel marine-derived oligosaccharide, acts as a heparanase inhibitor. Our results revealed that JG3 significantly inhibited tumor angiogenesis and metastasis, both in vitro and in vivo, by combating heparanase activity via binding to the KKDC and QPLK domains of the heparanase molecule. The JG3-heparanase interaction was competitively inhibited by low molecular weight heparin (4,000 Da) but not by other glycosaminoglycans. In addition, JG3 abolished heparanase-driven invasion, inhibited the release of heparan sulfate-sequestered basic fibroblast growth factor (bFGF) from the extracellular matrix, and repressed subsequent angiogenesis. Moreover, JG3 inactivated bFGF-induced bFGF receptor and extracellular signal-regulated kinase 1/2 phosphorylation and blocked bFGF-triggered angiogenic events by directly binding to bFGF. Thus, JG3 seems to inhibit both major heparanase activities by simultaneously acting as a substrate mimetic and as a competitive inhibitor of heparan sulfate. These findings suggest that JG3 should be considered as a promising candidate agent for cancer therapy.

• Authors: Huajun Zhao, Haiying Liu, Yi Chen, Xianliang Xin, Jing Li, Yongtai Hou, Zhonghua Zhang, Xiongwen Zhang, Chengying Xie, Meiyu Geng, Jian Ding
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 17 Pg. 8779-87 (Sep 01 2006) ISSN: 1538-7445 [Electronic] United States
• PMID: 16951194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Enzyme Inhibitors
• Mannans
• oligomannurarate sulfate
• Fibroblast Growth Factor 2
• heparanase
• Glucuronidase

Topics

• Allantois (drug effects, physiology)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Aorta
• Cattle
• Cell Movement (drug effects)
• Chorion (drug effects, physiology)
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Fibroblast Growth Factor 2 (drug effects, metabolism, physiology)
• Glucuronidase (antagonists & inhibitors)
• Humans
• Mannans (pharmacology)
• Muscle, Smooth, Vascular (drug effects, physiology)
• Neoplasm Invasiveness (prevention & control)
• Neoplasm Metastasis (prevention & control)
• Neovascularization, Pathologic (prevention & control)
• Rats
• Surface Plasmon Resonance