TW-01, a piperazinedione-derived compound, inhibits Ras-mediated cell proliferation and angioplasty-induced vascular restenosis.
Vascular smooth muscle cell (VSMC) proliferation plays a critical role in the pathogenesis of atherosclerosis and restenosis. This study investigated piperazinedione derived compound TW-01-mediated inhibitory effects on VSMC proliferation and intimal hyperplasia.



Cell proliferation was determined using [(3)H]-thymidine incorporation and MTT assay; cell cycle distribution was measured using flow cytometry; proteins and mRNA expression were determined using western blotting and RT-PCR analyses; DNA binding activity of nuclear factor-κB (NF-κB), as measured using enzyme-linked immunosorbent assays (ELISA); in vivo effects of TW-01 were determined using balloon angioplasty in the rat.



TW-01 significantly inhibited cell proliferation. At the concentrations used, no cytotoxic effects were observed. Three predominant signaling pathways were inhibited by TW-01: (a) extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) activation and its downstream effectors of c-fos, c-jun, and c-myc; (b) DNA binding activity of nuclear factor-κB (NF-κB); and, (c) Akt/protein kinase B (PKB) and cell cycle progression. Furthermore, TW-01 also inhibited Ras activation, a shared upstream event of each of these signaling cascades. In vascular injury studies, oral administration of TW-01 significantly suppressed intimal hyperplasia induced by balloon angioplasty.



The present study suggests that TW-01 might be a potential candidate for atherosclerosis treatment.
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City, Taiwan; Division of Cardiology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
Chao-Feng
CF
Lin
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
Han-Li
HL
Huang
Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan; School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan.
Chieh-Yu
CY
Peng
The Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Biotechnology in Medicine, Taipei Medical University, Taipei, Taiwan.
Yu-Ching
YC
Lee
College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
Hui-Po
HP
Wang
College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Che-Ming
CM
Teng
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 10031, Taiwan. Electronic address: slpan@tmu.edu.tw.
Shiow-Lin
SL
Pan
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D017536:Carotid Artery, Common / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000188:drug therapy*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054659:Diketopiperazines / Q000494:pharmacology / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006965:Hyperplasia / Q000188:drug therapy*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D017208:Rats, Wistar; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D018631:ras Proteins / Q000037:antagonists & inhibitors
D054659:Diketopiperazines; D016328:NF-kappa B; D011725:Pyridines; C000619493:TW-01 compound; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins; D006152:Cyclic GMP
Angioplasty; Atherosclerosis; Proliferation; Restenosis; TW-01; Vascular smooth muscle cell