TW-01, a piperazinedione-derived compound, inhibits Ras-mediated cell proliferation and angioplasty-induced vascular restenosis

Chao Feng Lin, Han Li Huang, Chieh Yu Peng, Yu Ching Lee, Hui Po Wang, Che Ming Teng, Shiow Lin Pan

Research output: Contribution to journalArticle

Abstract

Purpose 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. Methods Cell proliferation was determined using [3H]-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. Results 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. Conclusion The present study suggests that TW-01 might be a potential candidate for atherosclerosis treatment.

Original languageEnglish
Pages (from-to)194-202
Number of pages9
JournalToxicology and Applied Pharmacology
Volume305
DOIs
Publication statusPublished - Aug 15 2016

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Keywords

  • Angioplasty
  • Atherosclerosis
  • Proliferation
  • Restenosis
  • TW-01
  • Vascular smooth muscle cell

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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