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

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 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.

1,4-Naphthoquinones: From Oxidative Damage to Cellular and Inter-Cellular Signaling

“…Interestingly, RTK signaling may also be impaired by suitable naphthoquinones: PDGFR inhibitors on a naphthoquinone basis were synthesized and described recently, targeting PDGFR but not EGFR signaling in vascular smooth muscle cells. These quinones are 5,8-dimethoxy-1, 4-naphthoquinone derivatives with intermediate-chain alkyl moieties (nonylamino [39], decylamino [40] and undecylsulfonyl [41]) in position 2—quite different from the short-chain derivatives in Table 1.…”

Sesamin Inhibits PDGF-Mediated Proliferation of Vascular Smooth Muscle Cells by Upregulating p21 and p27

“…Immunoblotting was performed as described previously with slight modifications. , VSMCs were stimulated with 50 ng/mL PDGF-BB to trigger phosphorylation of JNK (3 min poststimulation [ps]); ERK 1/2 (5 min ps); p38 and PDGF-Rβ (10 min ps); PLCγ1, STAT3, and Akt (15 min ps). Cells were stimulated with 50 ng/mL PDGF-BB for 24 h prior to evaluation of cyclin D1, cyclin E, CDK2, CDK4, PCNA, p21 CIP , p27 KIP , and p53 expression levels; the extent of PARP cleavage; and the pRb phosphorylation level.…”

“…Entry of VSMCs into the cell cycle plays an important role in the development and progression of cellular proliferation. Thus, regulation of the cell cycle is a key strategy when it is sought to inhibit cellular proliferation. − …”

2-cyclohexylamino-5,8-dimethoxy-1,4-naphthoquinone inhibits LPS-induced BV2 microglial activation through MAPK/NF-kB signaling pathways

“…As a consequence, the molecular framework of many pharmaceuticals and biologically important compounds contain a quinine moiety. The 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) used as common start compound to synthesize Naphthoquinone derivatives, and it was reported that DMNQ derivatives exhibit the anti-tumor activity in breast cancers [ 15 , 16 ], and could also prevent cell proliferations through regulating the cellular MAPK and PI3 K signaling pathways [ 17 , 18 ]. But the inhibitory effect of naphthoquinone derivatives on the LPS-induced activation of microglial cells is not yet understood.…”