Antiproliferative mechanisms of raxofelast (IRFI-016) in H 2O2-stimulated rat aortic smooth muscle cells

Kyung Hye Lee, So Yeon Lim, Seok Min Kang, Dae Hyeok Kim, Hong Keun Cho, Ji Hyung Chung, Hyuck Moon Kwon, Kwang Hoe Chung, Hakbae Lee, Yangsoo Jang, Ki Chul Hwang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Reactive oxygen species-mediated cellular injury is involved in the pathogenesis of many diseases, including those affecting the cardiovascular system, such as myocardial ischemia-reperfusion injury, inflammation, and atheroscleosis. Raxofelast (IRFI-016; (±)-5-acetoxy-2, 3-dihydro-4, 6, 7-trimethyl-2-benzofuran-acetic acid) was designed with the aim of maximizing the antioxidant potency of phenols chemically related to vitamin E. The antioxidant activity of raxofelast has been convincingly demonstrated in several in vitro studies and in various models of ischemia-reperfusion injury. In this study, the antiproliferative effects of raxofelast were investigated to determine whether transduction signals and protooncogenes are affected in H 2O2-stimulated rat aortic smooth muscle cells. In a tetrazolium-based colorimetric assay, the proliferation of rat aortic smooth muscle cells was increased by 3-fold in 0.1% fetal bovine serum/Dulbecco's modified Eagle's medium (DMEM) containing 500 μM H2O2, indicating that exogenous 500 μM H2O2 was a growth stimulator of rat aortic smooth muscle cells. Exogenous H2O 2 significantly activated extracellular signal-regulated kinases (ERKs) activity within 30 min and raxofelast inhibited the ERKs activation dose dependently in 500 μM H2O2-stimulated rat aortic smooth muscle cells (IC50: 200 μM). Raxofelast reduced the intracellular reactive oxygen species generated by exogenous H2O 2 in a dose-dependent manner. In 500 μM H2O 2-stimulated rat aortic smooth muscle cells, raxofelast dramatically attenuated the activation of mitogen-activating protein kinase (MAPK)/ERK kinase 1, 2 (MEK1,2) and protein kinase C (PKC) without affecting Ras expression. Induction of c-myc mRNA was significantly reduced dose dependently up to 100 μM by raxofelast in concentrations. These data indicate that the antiproliferative effects of raxofelast in H2O2- stimulated rat aortic smooth muscle cells may involve the suppression of intracellular reactive oxygen species formation and the inhibition of ERKs by inactivation through PKC and MEK1,2 and down-regulation of c-myc expression, regardless of Ras activation.

Original languageEnglish
Pages (from-to)119-125
Number of pages7
JournalEuropean Journal of Pharmacology
Volume484
Issue number2-3
DOIs
Publication statusPublished - 2004 Jan 26

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this