title: Chemically synthesized matrix metalloproteinase and angiogenesis-inhibiting peptides as anticancer agents.
abstract: By connection of Regasepin2, a heptapeptide inhibitor of matrix metalloproteinases (MMPs), to the N- or C-terminus of ES-2, an anti-angiogenic peptide of 11 residues, two designed peptides CPU1 and CPU2 were generated. Unexpectedly, CPU2 inhibited MMP-8 and MMP-9 activity in the nanomolar range, whereas CPU1 displayed a weaker inhibitory profile than Regasepin2 against TACE, MMP-8 and MMP-9. CPU1 showed a higher affinity than CPU2 with integrin α5β1 in a HUVEC adhesion assay. In an in vitro angiogenesis model of HUVEC migration, CPU1 showed higher inhibition potency than CPU2 (85% inhibition for CPU1 at a concentration of 0.8 μM versus 17% inhibition for CPU2 at the same concentration). In an in vivo angiogenesis model in chicken egg chorioallantoic membranes, 1.37 μM CPU1 showed a significant inhibition in the formation of new blood vessels, whereas CPU2 and Regasepin2 had no effect on angiogenesis. Furthermore, CPU1 significantly inhibited B16F10 melanoma growth in a syngeneic mouse model (inhibition rate of 56.91% by tumor weight analysis at a dose of 20 mg/kg/d), whereas CPU2 and Regasepin2 did not show any inhibitory effect. In view of recent findings that MMP-9 is pro-angiogenic, our results indicated that the combination of MMP inhibitors and anti-angiogenic peptides may generate novel molecules with potent in vivo anti-tumor effects.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Hu
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Chunyan
authors.initials: C
authors.lastname: Pu
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.forename: Philippe E
authors.initials: PE
authors.lastname: Van den Steen
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.affiliation: The Key Laboratory of Modern Chinese Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China. xuhanmei@cpu.edu.cn.
authors.forename: Hanmei
authors.initials: H
authors.lastname: Xu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D039081:Integrin alpha5beta1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009336:Necrosis; D009368:Neoplasm Transplantation; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D039081:Integrin alpha5beta1; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9