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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aziridines / chemical synthesis
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Aziridines / pharmacology*
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Cell Line, Tumor
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Cell Movement / drug effects
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Collagen
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Diffusion Chambers, Culture
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Drug Combinations
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Gene Expression Regulation, Neoplastic*
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / enzymology
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Humans
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Laminin
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism*
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Matrix Metalloproteinase Inhibitors / chemical synthesis
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Matrix Metalloproteinase Inhibitors / pharmacology*
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Melanoma, Experimental / drug therapy
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Melanoma, Experimental / enzymology
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Melanoma, Experimental / genetics
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Melanoma, Experimental / pathology
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Mice
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / enzymology
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / pathology
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Phosphorylation / drug effects
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Proteoglycans
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Signal Transduction
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Tetradecanoylphorbol Acetate / analogs & derivatives
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Tetradecanoylphorbol Acetate / pharmacology
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Triazoles / chemical synthesis
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Triazoles / pharmacology*
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Aziridines
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Drug Combinations
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JaZ-30 compound
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Laminin
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Matrix Metalloproteinase Inhibitors
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Proteoglycans
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Triazoles
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Vascular Endothelial Growth Factor A
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matrigel
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phorbolol myristate acetate
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Collagen
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Matrix Metalloproteinase 2
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Tetradecanoylphorbol Acetate