A novel matrix metalloproteinase-2 inhibitor triazolylmethyl aziridine reduces melanoma cell invasion, angiogenesis and targets ERK1/2 phosphorylation

J Enzyme Inhib Med Chem. 2014 Dec;29(6):765-72. doi: 10.3109/14756366.2013.855207. Epub 2013 Nov 19.

Abstract

A novel matrix metalloproteinase-2 (MMP-2) inhibitor JaZ-30, which belongs to the class of C(2)-monosubstituted aziridine - aryl-1,2,3-triazole conjugates, was developed. MTT and crystal violet assays were used to determine cytotoxicity- IC(50) values of compound JaZ-30 on melanoma cell line B16 4A5. Our study proves the anti-cancer properties of JaZ-30 with a wide spectrum of activities. JaZ-30 was revealed as selective inhibitor of matrix metalloproteinase-2. JaZ-30-mediated decrease of Vascular Endothelial Growth Factor (VEGF) secretion results in inhibition of angiogenesis, performed with the human umbilical vein endothelial cell line (HUVEC-2) on Matrigel. A novel inhibitor decreases invasive properties of melanoma cells measured in Matrigel chambers assay. JaZ-30 downregulates phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in melanoma cells stimulated by phorbol-12-myristate-13-acetate (PMA). Our findings propose a novel MMP-2 inhibitor JaZ-30 as an attractive potential agent for melanoma treatment.

Keywords: Angiogenesis; aziridine-triazole conjugate; drug discovery; invasion; matrix metalloproteinase inhibitor; melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aziridines / chemical synthesis
  • Aziridines / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Collagen
  • Diffusion Chambers, Culture
  • Drug Combinations
  • Gene Expression Regulation, Neoplastic*
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / enzymology
  • Humans
  • Laminin
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / enzymology
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / pathology
  • Mice
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / enzymology
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / pathology
  • Phosphorylation / drug effects
  • Proteoglycans
  • Signal Transduction
  • Tetradecanoylphorbol Acetate / analogs & derivatives
  • Tetradecanoylphorbol Acetate / pharmacology
  • Triazoles / chemical synthesis
  • Triazoles / pharmacology*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Aziridines
  • Drug Combinations
  • JaZ-30 compound
  • Laminin
  • Matrix Metalloproteinase Inhibitors
  • Proteoglycans
  • Triazoles
  • Vascular Endothelial Growth Factor A
  • matrigel
  • phorbolol myristate acetate
  • Collagen
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Matrix Metalloproteinase 2
  • Tetradecanoylphorbol Acetate