Pharmacological inhibitors of NAD(P)H quinone oxidoreductase, NQO1: structure/activity relationships and functional activity in tumour cells.
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.
Nolan
Karen Ann
KA
School of Pharmacy and Pharmaceutical Sciences, University of Manchester and Manchester Cancer Research, Manchester, Oxford Road, Manchester, M13 9PT, UK.
Scott
Katherine Ann
KA
Barnes
John
J
Doncaster
Jeremy
J
Whitehead
Roger Clive
RC
Stratford
Ian James
IJ
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001388:Aziridines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001728:Dicumarol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D045563:Indolequinones / Q000494:pharmacology; D009243:NAD / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D009369:Neoplasms; D011506:Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D009243:NAD; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C060817:apaziquone