Anti-invasive activity of synthetic serine protease inhibitors and its combined effect with a matrix metalloproteinase inhibitor.
Tumor invasion into the extracellular matrix (ECM) and basement membrane (BM) is a crucial step of tumor metastasis. In order to investigate the possible therapeutic procedure for the tumor invasion, we investigated the anti-invasive activities of several synthetic serine protease inhibitors. FOY-305, a serine protease inhibitor, showed no cytotoxic activity against human HT-1080 fibrosarcoma cells at concentrations ranging from 0.1 to 100 micrograms/ml, while its analogs ONO-3403 and FO-349 showed slight cytotoxic activities at the concentration of 100 micrograms/ml. These compounds inhibited the activity of urokinase-type plasminogen activator (u-PA) which is one of serine proteases and considered to be associated with tumor invasion and metastasis in fibrin zymography. FOY-305 more potently inhibited the invasion of HT-1080 cells into the reconstituted BM Matrigel, as well inhibited u-PA activity, compared with ONO-3403 and FO-349. These results suggest that the anti-invasive activity of these compounds is consistent with their anti-fibrinolytic activities. In addition, the combined treatment of FOY-305 with FC-336 processing anti-invasive and anti-MMP properties resulted in marked enhancement of anti-invasive activity. In conclusion, FOY-305 inhibited the invasion of tumor cells through interference with the u-PA activity of tumor cells, and this inhibitory activity was augmented by the combination with a MMP inhibitor.
Ikeda
T
T
Department of Pathogenic Biochemistry, Toyama Medical and Pharmaceutical University, Japan.
Murakami
K
K
Hayakawa
Y
Y
Fujii
H
H
Ohkoshi
M
M
Saiki
I
I
D000501:Allylglycine / Q000031:analogs & derivatives* / Q000633:toxicity; D000578:Amidines / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D001550:Benzamidines / Q000633:toxicity*; D001565:Benzoates / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004952:Esters; D005354:Fibrosarcoma / Q000473:pathology*; D016670:Gabexate / Q000031:analogs & derivatives*; D006146:Guanidines / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D015842:Serine Proteinase Inhibitors / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
D000578:Amidines; D000970:Antineoplastic Agents; D001550:Benzamidines; D001565:Benzoates; D004952:Esters; D006146:Guanidines; C116985:ONO-FO 349-01; D015842:Serine Proteinase Inhibitors; C100807:ethyl N-allyl-N-(2-methyl-3-(4-(4-amidinophenoxycarbonyl)phenyl)propenoyl)aminoacetate methanesulfonate; C034532:camostat; D000501:Allylglycine; D016670:Gabexate; D014568:Urokinase-Type Plasminogen Activator