title: U0126 protects cells against oxidative stress independent of its function as a MEK inhibitor.
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.
authors.affiliation: Department of Chemistry, Stanford University , 380 Roth Way, Palo Alto, California 94305, United States.
authors.forename: Qunxiang
authors.initials: Q
authors.lastname: Ong
authors.forename: Shunling
authors.initials: S
authors.lastname: Guo
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: Bianxiao
authors.initials: B
authors.lastname: Cui
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008279:Magnetic Resonance Imaging; D009570:Nitriles / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D017382:Reactive Oxygen Species; C113580:U 0126; D006861:Hydrogen Peroxide; D020930:MAP Kinase Kinase Kinases
keywords: MEK inhibitor; U0126; antioxidant; cell death; oxidative stress