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: Jialiang Hu, Ming Yan, Chunyan Pu, Jingjing Wang, Philippe E Van den Steen, Ghislain Opdenakker, Hanmei Xu
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 14 Issue 3 Pg. 483-94 (Mar 2014) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 24533654 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Integrin alpha5beta1
• Matrix Metalloproteinase Inhibitors
• Peptides
• Matrix Metalloproteinases
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Angiogenesis Inhibitors (chemical synthesis, pharmacology)
• Animals
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Chick Embryo
• Chorioallantoic Membrane (blood supply, drug effects)
• Human Umbilical Vein Endothelial Cells (drug effects, physiology)
• Integrin alpha5beta1 (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors (chemical synthesis, pharmacology)
• Matrix Metalloproteinases (metabolism)
• Melanoma, Experimental (drug therapy, pathology)
• Mice
• Necrosis
• Neoplasm Transplantation
• Peptides (chemical synthesis, pharmacology)