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Gabexate Mesilate Inhibits Colon Cancer Growth, Invasion, and Metastasis by Reducing Matrix Metalloproteinases and Angiogenesis

Departments of ¹ Surgery, ² Biochemistry, and ³ Pathology, ⁴ Cancer Research Institute, Chungnam National University College of Medicine, Daejon, Korea; ⁵ Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejon, Korea; and ⁶ Gastrointestinal Research Laboratory, Veterans Administration Medical Center, Department of Medicine and Pathology, University of California, San Francisco, California

Gabexate mesilate (GM), a synthetic protease inhibitor, has an antiproteinase activity on various types of plasma serine proteases. However, its role on matrix metalloproteinases (MMPs) has not been identified. In this study, we investigated the effect of GM on MMPs and on the invasion and metastasis of human colon cancer cell lines and neoangiogenesis. The activities of MMPs secreted from these cells were significantly reduced by GM but unaffected by the serine protease inhibitor aprotinin. GM directly inhibited purified progelatinase A derived from T98G human glioblastoma cells. In vitro, GM significantly reduced the invasive ability of colon cancer cells but not cellular motility, whereas aprotinin affected neither. Liver metastatic ability and tumorigenic potential in nude mice were remarkably reduced on treatment with GM. Immunohistochemical analysis of GM-treated tumors in mice showed a marked increase in apoptosis and a significant reduction in tumor angiogenesis. Human umbilical vein endothelial cell proliferation, tube formation, and neoangiogenesis in the rabbit cornea and Matrigel implanted in mice were significantly inhibited by GM. These results suggest that GM is a novel inhibitor of MMPs and that it may inhibit the invasion and metastasis of human colon cancer cells by blocking MMPs and neoangiogenesis.

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