Inhibition of Ras-mediated cell proliferation by benzyloxybenzaldehyde.
Excessive proliferation of vascular smooth muscle cells (VSMC) in the intima is an important etiologic factor in vascular proliferative disorders such as atherosclerosis and restenosis after balloon angioplasty. Therefore, control of VSMC growth may be a suitable therapeutic intervention in vascular proliferative disorders. In the present work, we have studied the 2-benzyloxybenzaldehyde (CCY1a)-mediated antiproliferative effect and its mechanisms of action. CCY1a inhibited serum-induced VSMC proliferation in a concentration-dependent manner, as demonstrated using [(3)H]thymidine incorporation and MTT assays; the IC(50) values were calculated to be 7.0 x 10(-6) and 1.2 x 10(-5) M, respectively. Furthermore, it also significantly suppressed serum-induced progression of the cell cycle, as shown by flow cytometric analysis. CCY1a as well as PD98059 almost completely abolished serum-induced activation of p42/44 mitogen-activated protein kinase (MAPK), the downstream effectors of c-fos and c-jun mRNA expression and activator protein-1 (AP-1) DNA binding activity, suggesting the central roles of these signaling cascades. Interestingly, CCY1a also effectively blocked serum-induced Ikappa B-alpha phosphorylation, Ikappa B-alpha degradation and nuclear factor-kappa B (NF-kappa B) binding activity. Based on these observations, we examined the effect of CCY1a on serum-mediated Ras activity, an upstream regulator of the above signaling events. The data demonstrated a marked inhibition of Ras activation by CCY1a. We conclude that CCY1a blocks cell proliferation via inhibition of the upstream effector of Ras and downstream events, including p42/44 MAPK activation and c-fos and c-jun mRNA expression, as well as NF-kappa B and AP-1 DNA binding activities.
Pan
Shiow-Lin
SL
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Guh
Jih-Hwa
JH
Huang
Ying-Wen
YW
Chang
Ya-Ling
YL
Chang
Chiung-Yun
CY
Huang
Li-Jiau
LJ
Kuo
Sheng-Chu
SC
Teng
Che-Ming
CM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001011:Aorta; D001547:Benzaldehydes / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017781:Genes, Immediate-Early / Q000187:drug effects; D020935:MAP Kinase Signaling System; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D016328:NF-kappa B / Q000187:drug effects; D051381:Rats; D018808:Transcription Factor AP-1 / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
C468728:2-benzyloxybenzaldehyde; D000970:Antineoplastic Agents; D001547:Benzaldehydes; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D018631:ras Proteins