Inhibitors of NQO1: identification of compounds more potent than dicoumarol without associated off-target effects.
The enzyme NAD(P)H quinone oxidoreductase (NQO1) can function both as a detoxifying enzyme as well as chaperone protein. The latter property has been extensively characterized by the use of dicoumarol which inhibits the chaperone properties of NQO1 in cells. However, the use of this compound is compromised by its multiple "off-target" effects. Coumarin-based compounds that are more potent than dicoumarol as inhibitors of NQO1 in cells have been identified (Nolan et al., Biochem Pharmacol 2010;80:977-81). The purpose of the work reported here is to evaluate the off-target effects of these compounds when compared to dicoumarol. A range of these substituted coumarins are identified that are significantly less toxic than dicoumarol in a panel of nine cell lines. Further a number of the compounds generate much less intracellular superoxide, and many of them also show a reduced ability to induce apoptosis when compared to dicoumarol. None of these effects correlate with the ability of the compounds to inhibit the enzymatic activity of NQO1 in cells. In conclusion, potent inhibitors of NQO1 have been identified that will be more pharmacologically useful than dicoumarol for probing the function of NQO1 in cells and tissues.
Scott
Katherine Ann
KA
School of Pharmacy and Pharmaceutical Sciences, University of Manchester and Manchester Cancer Research Centre, Oxford Road, Manchester, UK.
Barnes
John
J
Whitehead
Roger Clive
RC
Stratford
Ian James
IJ
Nolan
Karen Ann
KA
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D001728:Dicumarol / Q000031:analogs & derivatives / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D004791:Enzyme Inhibitors; D013481:Superoxides; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human