U0126 protects cells against oxidative stress independent of its function as a MEK inhibitor

ACS Chem Neurosci. 2015 Jan 21;6(1):130-7. doi: 10.1021/cn500288n. Epub 2015 Jan 6.

Abstract

U0126 is a potent and selective inhibitor of MEK1 and MEK2 kinases. It has been widely used as an inhibitor for the Ras/Raf/MEK/ERK signaling pathway with over 5000 references on the NCBI PubMed database. In particular, U0126 has been used in a number of studies to show that inhibition of the Raf/MEK/ERK pathway protects neuronal cells against oxidative stress. Here, we report that U0126 can function as an antioxidant that protects PC12 cells against a number of different oxidative-stress inducers. This protective effect of U0126 is independent of its function as a MEK inhibitor, as several other MEK inhibitors failed to show similar protective effects. U0126 reduces reactive oxygen species (ROS) in cells. We further demonstrate that U0126 is a direct ROS scavenger in vitro, and the oxidation products of U0126 exhibit fluorescence. Our finding that U0126 is a strong antioxidant signals caution for its future usage as a MEK inhibitor and for interpreting some previous results.

Keywords: MEK inhibitor; U0126; antioxidant; cell death; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butadienes / pharmacology*
  • Cell Death / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Hydrogen Peroxide / toxicity
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Magnetic Resonance Imaging
  • Nitriles / pharmacology*
  • Oxidative Stress / drug effects*
  • PC12 Cells
  • Phosphorylation / drug effects
  • Rats
  • Reactive Oxygen Species / metabolism
  • Time Factors

Substances

  • Butadienes
  • Enzyme Inhibitors
  • Nitriles
  • Reactive Oxygen Species
  • U 0126
  • Hydrogen Peroxide
  • MAP Kinase Kinase Kinases