1. Pharmacological inhibitors of NAD(P)H quinone oxidoreductase, NQO1: structure/activity relationships and functional activity in tumour cells.
- Author
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Nolan KA, Scott KA, Barnes J, Doncaster J, Whitehead RC, and Stratford IJ
- Subjects
- Antineoplastic Agents antagonists & inhibitors, Antineoplastic Agents pharmacology, Aziridines antagonists & inhibitors, Aziridines pharmacology, Dicumarol antagonists & inhibitors, Dicumarol pharmacology, Humans, Indolequinones pharmacology, NAD antagonists & inhibitors, NAD metabolism, NAD pharmacology, NAD(P)H Dehydrogenase (Quinone) pharmacology, Neoplasms, Proteins antagonists & inhibitors, Proteins pharmacology, Structure-Activity Relationship, Tumor Suppressor Protein p53 antagonists & inhibitors, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 pharmacology, NAD(P)H Dehydrogenase (Quinone) antagonists & inhibitors, NAD(P)H Dehydrogenase (Quinone) metabolism
- Abstract
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., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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