5,8-Dimethoxy-2-Nonylamino-Naphthalene-1,4-Dione Inhibits Vascular Smooth Muscle Cell Proliferation by Blocking Autophosphorylation of PDGF-Receptor β

As the abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis and vascular restenosis, a candidate drug with antiproliferative properties is needed. We investigated the antiproliferative action and underlying mechanism of a newly synthesized naphthoquinone derivative, 5,8-dimethoxy-2-nonylamino-naphthalene-1,4-dione (2-nonylamino-DMNQ), using VSMCs treated with platelet-derived growth factor (PDGF). 2-Nonylamino-DMNQ inhibited proliferation and cell number of VSMCs induced by PDGF, but not epidermal growth factor (EGF), in a concentration-dependent manner without any cytotoxicity. This derivative suppressed PDGF-induced [3H]-thymidine incorporation, cell cycle progression from G0/G1 to S phase, and the phosphorylation of phosphor-retinoblastoma protein (pRb) as well as the expression of cyclin E/D, cyclin-dependent kinase (CDK) 2/4, and proliferating cell nuclear antigen (PCNA). Importantly, 2-nonylamino-DMNQ inhibited the phosphorylation of PDGF receptorβ(PDGF-Rβ) enhanced by PDGF at Tyr579, Tyr716, Tyr751, and Tyr1021 residues. Subsequently, 2-nonylamino-DMNQ inhibited PDGF-induced phosphorylation of STAT3, ERK1/2, Akt, and PLCγ1. Therefore, our results indicate that 2-nonylamino-DMNQ inhibits PDGF-induced VSMC proliferation by blocking PDGF-Rβ autophosphorylation, and subsequently PDGF-Rβ-mediated downstream signaling pathways.

• Publication year

  2013

• Venue

  Korean Journal of Physiology and Pharmacology

• Publication date

  2013-06-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.4196/kjpp.2013.17.3.203PMID 23776396PMCID 3682080
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2002cited by this paper
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  2002cited by this paper
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  2002cited by this paper
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  2001cited by this paper
• Growth inhibition and protein tyrosine phosphorylation in MCF 7 breast cancer cells by a novel K vitamin

  2000cited by this paper
• Phosphatidylinositol 3-kinase is required for growth factor-induced amino acid uptake by vascular smooth muscle cells.

  1999cited by this paper
• Inhibition of 2-P-mercaptophenyl-1,4-naphthoquinone on human platelet function.

  1999cited by this paper
• Quinones increase γ-glutamyl transpeptidase expression by multiple mechanisms in rat lung epithelial cells.

  1998cited by this paper
• PDGF-receptor tyrosine kinase blocker AG1295 selectively attenuates smooth muscle cell growth in vitro and reduces neointimal formation after balloon angioplasty in swine.

  1998cited by this paper
• Signal transduction: New exchange, new target

  1998cited by this paper
• Modulation of Ca2+-gated cardiac muscle Ca2+-release channel (ryanodine receptor) by mono- and divalent ions.

  1998cited by this paper
• Gangliosides GM1, GM2 and GM3 inhibit the platelet-derived growth factor-induced signalling transduction pathway in vascular smooth muscle cells by different mechanisms.

  1996cited by this paper
• An antifungal naphthoquinone, xanthones and secoiridoids from Swertia calycina.

  1995cited by this paper
• Cell biology of atherosclerosis.

  1995cited by this paper
• Tyr-716 in the platelet-derived growth factor beta-receptor kinase insert is involved in GRB2 binding and Ras activation

  1994cited by this paper
• Platelet-derived growth factor receptor signals.

  1994cited by this paper
• Quinone-induced oxidative stress elevates glutathione and induces gamma-glutamylcysteine synthetase activity in rat lung epithelial L2 cells.

  1994cited by this paper
• Protein Tyrosine Kinase Inhibitors Inhibit Both Proliferation and Chemotaxis of Vascular Smooth Muscle Cells a

  1994cited by this paper
• Identification of two juxtamembrane autophosphorylation sites in the PDGF beta‐receptor; involvement in the interaction with Src family tyrosine kinases.

  1993cited by this paper
• Extracellular glutathione and gamma-glutamyl transpeptidase prevent H2O2-induced injury by 2,3-dimethoxy-1,4-naphthoquinone.

  1993cited by this paper
• Phosphorylation sites in the PDGF receptor with different specificities for binding GAP and PI3 kinase in vivo.

  1992influential reference
• Interaction of the p85 subunit of PI 3‐kinase and its N‐terminal SH2 domain with a PDGF receptor phosphorylation site: structural features and analysis of conformational changes.

  1992cited by this paper
• Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes.

  1991cited by this paper
• Inhibition of rabbit platelet aggregation by 1,4-naphthoquinones.

  1990cited by this paper
• Redox cycling and sulphydryl arylation; their relative importance in the mechanism of quinone cytotoxicity to isolated hepatocytes.

  1988cited by this paper
• Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation.

  1985cited by this paper
• The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. A study of the implications of oxidative stress in intact cells.

  1982cited by this paper
• Comparison of vascular smooth muscle cells from adult human, monkey and rabbit in primary culture and in subculture

  1977cited by this paper

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  2024cites this paper
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  2019cites this paper
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  2016cites this paper
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  2016cites this paper
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  2015cites this paper
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  2014cites this paper
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  2014cites this paper