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

다국어 초록 (Multilingual Abstract)

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 PDGFinduced 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.

참고문헌 (Reference)

1 Chlebowski RT, "Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation" 69 : 527-532, 1985

2 Dzau VJ, "Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies" 8 : 1249-1256, 2002

3 Arvidsson AK, "Tyr-716 in the platelet-derived growth factor β-receptor kinase insert is involved in GRB2 binding and Ras activation" 14 : 6715-6726, 1994

4 Dance M, "The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase(ERK1/2)pathway" 20 : 453-459, 2008

5 Bowman T, "Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis" 98 : 7319-7324, 2001

6 Downward J, "Signal transduction. New exchange, new target" 396 : 416-417, 1998

7 Tomita H, "Roxithromycin is an inhibitor of human coronary artery smooth muscle cells proliferation: a potential ability to prevent coronary heart disease" 182 : 87-95, 2005

8 Gant TW, "Redox cycling and sulphydryl arylation; their relative importance in the mechanism of quinone cytotoxicity to isolated hepatocytes" 65 : 157-173, 1988

9 Liu RM, "Quinones increase gamma-glutamyl transpeptidase expression by multiple mechanisms in rat lung epithelial cells" 274 : L330-L336, 1998

10 Shi MM, "Quinone-induced oxidative stress elevates glutathione and induces γ-glutamylcysteine synthetase activity in rat lung epithelial L2 cells" 269 : 26512-26517, 1994

11 Claesson-Welsh L, "Platelet-derived growth factor receptor signals" 269 : 32023-32026, 1994

12 Kashishian A, "Phosphorylation sites in the PDGF receptor with different specificities for binding GAP and PI3 kinase in vivo" 11 : 1373-1382, 1992

13 Higaki M, "Phosphatidylinositol 3-kinase is required for growth factor-induced amino acid uptake by vascular smooth muscle cells" 19 : 2127-2132, 1999

14 Banai S, "PDGF-receptor tyrosine kinase blocker AG1295 selectively attenuates smooth muscle cell growth in vitro and reduces neointimal formation after balloon angioplasty in swine" 97 : 1960-1969, 1998

15 Shimokado K, "Masuda proliferation and chemotaxis of vascular smooth muscle cells" 748 : 171-175, 1995

16 Panayotou G, "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" 11 : 4261-4272, 1992

17 Lee JJ, "Inhibitory effect of fenofibrate on neointima hyperplasia via G0/G1 arrest of cell proliferation" 650 : 342-349, 2011

18 Ko FN, "Inhibition of rabbit platelet aggregation by 1, 4-naphthoquinones" 57 : 453-463, 1990

19 Shen AY, "Inhibition of 2-p-mercaptophenyl-1, 4-naphthoquinone on human platelet function" 65 : 45-53, 1999

20 Schwaiberger AV, "Indirubin-3'-monoxime blocks vascular smooth muscle cell proliferation by inhibition of signal transducer and activator of transcription 3 signaling and reduces neointima formation in vivo" 30 : 2475-2481, 2010

21 Mori S, "Identification of two juxtamembrane autophosphorylation sites in the PDGF β-receptor; involvement in the interaction with Src family tyrosine kinases" 12 : 2257-2264, 1993

22 Kar S, "Growth inhibition and protein tyrosine phosphorylation in MCF 7 breast cancer cells by a novel K vitamin" 185 : 386-393, 2000

23 Sachinidis A, "Gangliosides GM1, GM2 and GM3 inhibit the platelet-derived growth factor-induced signalling transduction pathway in vascular smooth muscle cells by different mechanisms" 71 : 79-88, 1996

24 Shi M, "Extracellular glutathione and gamma-glutamyl transpeptidase prevent H2O2-induced injury by 2,3-dimethoxy-1,4-naphthoquinone" 15 : 57-67, 1993

25 Fang F, "Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes" 66 : 731-742, 1991

26 Beier I, "Epidermal growth factor stimulates Rac1 and p21-activated kinase in vascular smooth muscle cells" 196 : 92-97, 2008

27 Kingsley K, "ERK1/2 mediates PDGF-BB stimulated vascular smooth muscle cell proliferation and migration on laminin-5" 293 : 1000-1006, 2002

28 Moore GD, "Differential expression of cdk inhibitors p16, p21cip1, p27kip1, and cyclin E in cervical cytological smears prepared by the ThinPrep method" 32 : 82-87, 2005

29 Bailey SR, "Coronary restenosis : a review of current insights and therapies" 55 : 265-271, 2002

30 Chamley JH, "Comparison of vascular smooth muscle cells from adult human, monkey and rabbit in primary culture and in subculture" 177 : 503-522, 1977

31 Ross R, "Cell biology of atherosclerosis" 57 : 791-804, 1995

32 Lee JJ, "Anti-proliferative actions of 2-decylamino-5,8- dimethoxy-1,4-naphthoquinone in vascular smooth muscle cells" 411 : 213-218, 2011

33 Rodriguez S, "An antifungal naphthoquinone, xanthones and secoiridoids from Swertia calycina" 61 : 362-364, 1995

34 Thor H, "A study of the implications of oxidative stress in intact cells" 257 : 12419-12425, 1982

35 Lee JJ, "(2S)-naringenin from Typha angustata inhibits vascular smooth muscle cell proliferation via a G0/G1 arrest" 139 : 873-878, 2012