Oligomannurarate sulfate, a novel heparanase inhibitor simultaneously targeting basic fibroblast growth factor, combats tumor angiogenesis and metastasis.
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.
Zhao
Huajun
H
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
Liu
Haiying
H
Chen
Yi
Y
Xin
Xianliang
X
Li
Jing
J
Hou
Yongtai
Y
Zhang
Zhonghua
Z
Zhang
Xiongwen
X
Xie
Chengying
C
Geng
Meiyu
M
Ding
Jian
J
D000482:Allantois / Q000187:drug effects / Q000502:physiology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D002823:Chorion / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D006801:Humans; D008351:Mannans / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051381:Rats; D020349:Surface Plasmon Resonance; D000099175:Heparanase
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D008351:Mannans; D000099175:Heparanase; C524388:oligomannurarate sulfate