Cudratricusxanthone A isolated from the root bark of Cudrania tricuspidata inhibits the proliferation of vascular smooth muscle cells through the suppression of PDGF-receptor beta tyrosine kinase.
Platelet derived growth factor (PDGF)-BB is one of the most potent vascular smooth muscle cell (VSMC) proliferative factors, and abnormal VSMC proliferation by PDGF-BB plays an important role in the development and progression of cardiovascular problems, including restenosis after coronary angioplasty and atherosclerosis. Previous phytochemical studies on the stems or root barks of Cudrania tricuspidata (Moraceae) resulted in the isolation of various isoprenylated xanthones and flavonoids, some of which have anti-cancer, hepatoprotective, anti-inflammatory and anti-oxidant activities. In the present study, we investigated the antiproliferative effect of cudratricusxanthone A isolated from the root bark of C. tricuspidata and its underlying mechanism in VSMCs. Antiproliferative effects of cudratricusxanthone A on VSMCs were examined by direct cell counting and [3H]-thymidine incorporation assays. Cudratricusxanthone A inhibited [3H]-thymidine incorporations into DNA in VSMCs that occurred in response to treatment with 50 ng/ml PDGF-BB. PDGF-BB-stimulated DNA synthesis was significantly reduced to 86.1, 80.2, 64.2 and 25.1% at concentrations of 0.1, 1, 2 and 3 microM, respectively. Moreover, pre-treatment with cudratricusxanthone A (0.1-3 microM) suppressed this PDGF-BB-stimulated cell number in a concentration-dependent manner. The inhibition percentages were 11.1, 22.7, 51.3 and 81.5% at the concentrations of 0.1, 1, 2 and 3 microM, respectively. We also investigated the mechanism of antiproliferative effects by cudratricusxanthone A in PDGF-BB-stimulated VSMCs. In Western blot analysis, 50 ng/ml PDGF-BB-stimulated phospholipase C (PLC)gamma1, Ras, and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylations were inhibited by cudratricusxanthone A (0.1-3 microM). Consisted with these findings, cudratricusxanthone A inhibited PDGF-receptor beta chain (PDGF-Rbeta) phosphorylation induced by PDGF-BB in a concentration-dependent manner. These findings suggest that the inhibitory effects of cudratricusxanthone A on DNA synthesis and proliferation by PDGF-BB-stimulated VSMCs are mediated by the suppressions of the PDGF-Rbeta and its downstream signaling pathways. Our observation may explain in part mechanistic basis for the prevention of cardiovascular diseases, such as atherosclerosis and restenosis after coronary angioplasty by cudratricusxanthone A.
Kim
Tack-Joong
TJ
Research Center for Bioresource and Health, College of Pharmacy, Chungbuk National University, Korea.
Han
Hyeong-Jun
HJ
Hong
Seong-Su
SS
Hwang
Ji-Hye
JH
Hwang
Bang-Yeon
BY
Yoo
Hwan-Soo
HS
Jin
Yong-Ri
YR
Lee
Jung-Jin
JJ
Yu
Ji-Yeon
JY
Lee
Kwang-Ho
KH
Kang
Byoung-Won
BW
Yun
Yeo-Pyo
YP
D000818:Animals; D001011:Aorta / Q000166:cytology; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D008954:Models, Biological; D015394:Molecular Structure; D029586:Moraceae / Q000737:chemistry*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D024301:Plant Bark / Q000737:chemistry; D018517:Plant Roots / Q000737:chemistry; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013997:Time Factors; D044004:Xanthones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D016895:Culture Media, Serum-Free; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D044004:Xanthones; D000077214:Becaplermin; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor