A novel and selective membrane type-1 matrix metalloproteinase (MT1-MMP) inhibitor reduces cancer cell motility and tumor growth.
Matrix metalloproteinases (MMPs), and especially membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14), play a role in cancer progression and can have a prognostic value. Various synthetic broad-spectrum MMP inhibitors have been developed but have had little success in cancer patient treatment owing to side effects. Until recently, selective targeting of specific MMPs has not been possible due to lack of specific inhibitors. Here we have developed a selective MT1-MMP peptide-inhibitor GACFSIAHECGA, which did not affect the activities of many other MMPs including MMP-1, -2, -3, -7, -8, -9, -10, -11, -12, -13, -15, -17 or -20. In a fluorescent peptide cleavage assay it displayed an IC(50) value of 150 microM. The peptide effectively inhibited the migration and invasion of cancer cell lines in vitro. Furthermore, in vivo the peptide reduced the growth of tongue carcinoma xenografts and prolonged the survival of mice. Overall these results suggest that selective MT1-MMP inhibitors may have utility as anticancer agents.
Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Institute of Dentistry, University of Helsinki, Finland. juho.suojanen@helsinki.fi
Juho
J
Suojanen
Tuula
T
Salo
Erkki
E
Koivunen
Timo
T
Sorsa
Emma
E
Pirilä
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020128:Inhibitory Concentration 50; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology; D013997:Time Factors; D014062:Tongue Neoplasms / Q000378:metabolism / Q000473:pathology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D053511:Matrix Metalloproteinase 14