School of Pharmacy and Pharmaceutical Sciences, University of Manchester and Manchester Cancer Research, Manchester, Oxford Road, Manchester, M13 9PT, UK.
Biochem Pharmacol. 2010 Oct 1;80(7):977-81. doi: 10.1016/j.bcp.2010.06.024. Epub 2010 Jun 23.
NAD(P)H quinone oxidoreductase (NQO1) has multiple functions in the cell including an ability to act as a detoxifying enzyme and as a protein chaperone. The latter property is particularly important in oncology as one of the client proteins of NQO1 is p53. The inhibitor, dicoumarol, is classically used to probe the biological properties of NQO1, but interpretation of enzyme function is compromised by the multiple "off-target" effects of this agent. Coumarin-based compounds that are more potent than dicoumarol as inhibitors of recombinant human NQO1 have been identified (Nolan et al., J Med Chem 2009;52:7142-56) The purpose of the work reported here is to demonstrate the functional activity of these agents for inhibiting NQO1 in cells. To do this, advantage was taken of the NQO1-mediated toxicity of the chemotherapeutic drug EO9 (Apaziquone). The toxicity of this drug is substantially reduced when the function of NQO1 is inhibited and many of the coumarin-based compounds are more efficient than dicoumarol for inhibiting EO9 toxicity. The ability to do this appears to be related to their capacity to inhibit NQO1 in cell free systems. In conclusion, agents have been identified that may be more pharmacologically useful than dicoumarol for probing the function of NQO1 in cells and tissues.
NAD(P)H 醌氧化还原酶 (NQO1) 在细胞中具有多种功能，包括作为解毒酶和蛋白质伴侣的能力。后者的特性在肿瘤学中尤为重要，因为 NQO1 的一个客户蛋白是 p53。抑制剂，二香豆素，经典地用于探究 NQO1 的生物学特性，但由于该试剂的多种“非靶标”效应，对酶功能的解释受到了损害。已经鉴定出比二香豆素更能抑制重组人 NQO1 的香豆素类化合物（Nolan 等人，J Med Chem 2009；52:7142-56）。这里报告的工作的目的是证明这些试剂在细胞中抑制 NQO1 的功能活性。为此，利用化疗药物 EO9（Apaziquone）的 NQO1 介导的毒性来利用优势。当抑制 NQO1 的功能时，这种药物的毒性大大降低，许多香豆素类化合物比二香豆素更有效地抑制 EO9 毒性。这种能力似乎与其在无细胞系统中抑制 NQO1 的能力有关。总之，已经鉴定出一些试剂，它们在细胞和组织中探测 NQO1 的功能可能比二香豆素更具药理学用途。
