Ong Qunxiang, Guo Shunling, Zhang Kai, Cui Bianxiao
Department of Chemistry, Stanford University , 380 Roth Way, Palo Alto, California 94305, United States.
ACS Chem Neurosci. 2015 Jan 21;6(1):130-7. doi: 10.1021/cn500288n. Epub 2015 Jan 6.
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.
U0126是一种强效且具有选择性的MEK1和MEK2激酶抑制剂。它已被广泛用作Ras/Raf/MEK/ERK信号通路的抑制剂，在NCBI PubMed数据库中有超过5000篇相关参考文献。特别是，U0126已在多项研究中被用于表明抑制Raf/MEK/ERK通路可保护神经元细胞免受氧化应激。在此，我们报告U0126可作为一种抗氧化剂，保护PC12细胞免受多种不同氧化应激诱导剂的影响。U0126的这种保护作用与其作为MEK抑制剂的功能无关，因为其他几种MEK抑制剂未能显示出类似的保护作用。U0126可降低细胞中的活性氧（ROS）水平。我们进一步证明U0126在体外是一种直接的ROS清除剂，并且U0126的氧化产物具有荧光。我们发现U0126是一种强抗氧化剂，这为其未来作为MEK抑制剂的使用以及解释一些先前的结果敲响了警钟。
