Abstract
Imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate (NAMI-A) is a new ruthenium compound active against lung metastasis in vivo and tumor cell invasion in vitro. Since angiogenesis was recognized as a key event in the metastasizing process, the manipulation of neo-vessel formation has been developed as a new therapeutic approach. Within this context, a pivotal role for apoptosis in regulating cellular growth has been proposed. In the present study, we exposed to NAMI-A the spontaneously transformed human endothelial cell line ECV304 and assessed a number of apoptosis-related features, including the DNA degradation rate, the activation of caspase-3 protease, the expression of Hsp27, and the release of cytochrome c. Cell treatment with NAMI-A elicited a significant increment in the apoptotic response, as indicated by DNA fragmentation and caspase-3 activation, two classical hallmarks of cellular suicide. Furthermore, NAMI-A was able to down-regulate Hsp27 protein expression and provoke the release of mitochondrial cytochrome c in the cytosol. Here, we analyze the involvement of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signal transduction pathway in the induction of apoptosis elicited by NAMI-A. Such a response was associated with a marked inhibition of MAPK/ERK kinase (MEK) and ERK phosphorylation with a time course and dose dependency overlapping those observed throughout NAMI-A-induced apoptosis. In addition, we report that PD98059, a selective MEK inhibitor, is able to induce apoptosis by itself in the ECV304 cell line. These results suggest that inhibition of MEK/ERK signaling by NAMI-A may have an important role in modulating an apoptotic event in ECV304.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Apoptosis / physiology
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism
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Cell Transformation, Neoplastic
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Cells, Cultured
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Cytochrome c Group / metabolism
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DNA Fragmentation / drug effects
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Dimethyl Sulfoxide / analogs & derivatives*
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Dimethyl Sulfoxide / pharmacology*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Endothelium, Vascular / pathology*
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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HSP27 Heat-Shock Proteins
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Heat-Shock Proteins*
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Humans
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP Kinase Signaling System
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Mitogen-Activated Protein Kinase Kinases / drug effects
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism*
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Molecular Chaperones
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Neoplasm Proteins / drug effects
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Neoplasm Proteins / metabolism
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Oligopeptides / pharmacology
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Organometallic Compounds / pharmacology*
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Phosphorylation
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / drug effects
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Protein-Tyrosine Kinases / metabolism
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Ruthenium Compounds
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Signal Transduction
Substances
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Antineoplastic Agents
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Caspase Inhibitors
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Cytochrome c Group
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Enzyme Inhibitors
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Flavonoids
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HSP27 Heat-Shock Proteins
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HSPB1 protein, human
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Heat-Shock Proteins
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Molecular Chaperones
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Neoplasm Proteins
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Oligopeptides
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Organometallic Compounds
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Ruthenium Compounds
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aspartyl-glutamyl-valyl-aspartal
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imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III)
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MAP2K2 protein, human
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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CASP3 protein, human
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Caspase 3
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Caspases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Dimethyl Sulfoxide