Inhibitory effect of a novel naphthoquinone derivative on proliferation of vascular smooth muscle cells through suppression of platelet-derived growth factor receptor β tyrosine kinase.
This study was designed to investigate the antiproliferative effect of a novel naphthoquinone derivative, 2-undecylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (2-undecylsulfonyl-DMNQ), on platelet-derived growth factor (PDGF)-stimulated vascular smooth muscle cells (VSMCs) and examine the possible molecular mechanism of its antiproliferative action. 2-Undecylsulfonyl-DMNQ significantly inhibited PDGF-stimulated cell number and DNA synthesis, and arrested the PDGF-stimulated progression through G0/G1 to S phase of cell cycle supported by the suppression of pRb phosphorylation and cyclin D1/E, CDK2/4 and PCNA expressions. 2-Undecylsulfonyl-DMNQ dose-dependently inhibited the PDGF-stimulated phosphorylation of phospholipase Cγ (PLCγ), protein kinase B (Akt/PKB), signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK 1/2). In addition, 2-undecylsulfonyl-DMNQ inhibited PDGF-induced PDGF receptor β (PDGF-Rβ) dimerization and the phosphorylation of Tyr(579/581), Tyr(716), Tyr(751) and Tyr(1021) in PDGF-Rβ. However, 2-undecylsulfonyl-DMNQ has no antiproliferative effect on epidermal growth factor (EGF)- or fetal bovine serum (FBS)-stimulated VSMCs. In conclusion, these findings suggest that the antiproliferative effects of 2-undecylsulfonyl-DMNQ on PDGF-stimulated VSMCs are due to the blockade of receptor dimerization and autophosphorylation on specific tyrosine residues of PDGF-Rβ, which resulted in the subsequent suppression of signaling cascades and a cell cycle arrest. Our observation may explain an important mechanism to block the integration of multiple signals generated by growth factor receptor activation for prevention of VSMC proliferation in cardiovascular diseases.
Department of Pharmacology, Chungnam National University College of Pharmacy, 99 Daehakno, Yuseong-gu, Daejeon 305-764, Republic of Korea.
Yohan
Y
Kim
Department of Pharmacology, Chungnam National University College of Pharmacy, 99 Daehakno, Yuseong-gu, Daejeon 305-764, Republic of Korea.
Joo-Hui
JH
Han
Department of Medicinal Chemistry, Chungnam National University College of Pharmacy, Daejeon 305-764, Republic of Korea.
Eunju
E
Yun
Department of Pharmacology, Chungnam National University College of Pharmacy, 99 Daehakno, Yuseong-gu, Daejeon 305-764, Republic of Korea.
Sang-Hyuk
SH
Jung
Department of Pharmacology, Chungnam National University College of Pharmacy, 99 Daehakno, Yuseong-gu, Daejeon 305-764, Republic of Korea; Institute of Drug Research & Development, Chungnam National University, Daejeon 305-764, Republic of Korea.
Jung-Jin
JJ
Lee
Department of Medicinal Chemistry, Chungnam National University College of Pharmacy, Daejeon 305-764, Republic of Korea; Institute of Drug Research & Development, Chungnam National University, Daejeon 305-764, Republic of Korea.
Gyu-Yong
GY
Song
Department of Pharmacology, Chungnam National University College of Pharmacy, 99 Daehakno, Yuseong-gu, Daejeon 305-764, Republic of Korea; Institute of Drug Research & Development, Chungnam National University, Daejeon 305-764, Republic of Korea. Electronic address: cm8r@cnu.ac.kr.
Chang-Seon
CS
Myung
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D015151:Immunoblotting; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D055503:Protein Multimerization; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*
C000594165:2-undecylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone; D009285:Naphthoquinones; D013450:Sulfones; D004247:DNA; D020797:Receptor, Platelet-Derived Growth Factor beta
2-Undecylsulfonyl-DMNQ; Cardiovascular disease; Platelet-derived growth factor-receptor β; Proliferation; Vascular smooth muscle cell