Gabexate mesilate inhibits colon cancer growth, invasion, and metastasis by reducing matrix metalloproteinases and angiogenesis.
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.
Yoon
Wan-Hee
WH
Department of Surgery, Cancer Research Institute, Chungnam National University College of Medicine, Daejon, Korea. whyoon@cnu.ac.kr
Jung
Yeon-Joo
YJ
Kim
Tae-Dong
TD
Li
Ge
G
Park
Byoung-Jeon
BJ
Kim
Ji-Yeon
JY
Lee
Young-Chul
YC
Kim
Jin-Man
JM
Park
Jong-Il
JI
Park
Hae-Duck
HD
No
Zae-Sung
ZS
Lim
Kyu
K
Hwang
Byung-Doo
BD
Kim
Young S
YS
D000818:Animals; D002196:Capillaries / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D016670:Gabexate / Q000494:pharmacology*; D005782:Gels; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013696:Temperature; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis
D004338:Drug Combinations; D005782:Gels; D007797:Laminin; D011509:Proteoglycans; D015842:Serine Proteinase Inhibitors; C059485:matrigel; D016670:Gabexate; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9