title: Generation of antitumor peptides by connection of matrix metalloproteinase-9 peptide inhibitor to an endostatin fragment.
abstract: Previous applications of matrix metalloproteinase (MMP) inhibitors in cancer treatment have resulted in disappointing outcomes. Therefore, it is necessary to develop more active or better targeted MMP inhibitors. In this study, Inhibitor2, a heptapeptide MMP inhibitor, was connected to the N-terminus or C-terminus of ES-2, an 11-amino-acid antiangiogenic peptide, and two designed peptides, P2 and P4, were generated. P2 inhibited MMP-2, MMP-8, MMP-9, and tumor necrosis factor-α converting enzyme (TACE) activity with IC50 values of 1.40, 0.35, 1.36, and 1.95 μmol/l, whereas those for P4 were 19, 20, 18, and 18 μmol/l. P2 showed a higher affinity with integrin α5β1 in a human umbilical vein endothelial cell (HUVEC) adhesion assay than P4. In the HUVEC migration assay, P2 showed a better inhibitory effect on HUVEC migration than P4 and Inhibitor2 and the inhibitory ratio at 2 μg/ml was 77%. In a chorioallantoic membrane assay, at a concentration of 3.28 μg/ml, P2 and P4 showed 69.8 and 56.8% inhibition of formation of new blood vessels on the embryo membrane. Furthermore, P2 significantly inhibited B16F10 growth in a syngeneic mouse model with an inhibition ratio of 57.92% by tumor weight at a dose of 20 mg/kg/day, whereas P4 and Inhibitor2 exerted no such in-vivo effect. The antiangiogenic effect of P2 was confirmed by CD31 staining of the tumor tissue sections. The Inhibitor2 part of P2 may function both as an MMP inhibitor and as a targeting motif. These studies represented an example of how to better apply the potent and peptidomimetic MMP inhibitors in cancer treatment.
authors: The Key Laboratory of Modern Chinese Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, People's Republic of China.
authors: Zheng
authors: Z
authors: Qiu
authors: Jialiang
authors: J
authors: Hu
authors: Hanmei
authors: H
authors: Xu
authors: Wenjing
authors: W
authors: Wang
authors: Caihui
authors: C
authors: Nie
authors: Xiang
authors: X
authors: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D043169:Endostatins / Q000737:chemistry / Q000502:physiology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007313:Insecta; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000502:physiology*; D011897:Random Allocation
chemical_list: D000970:Antineoplastic Agents; D043169:Endostatins; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9