NAD(P)H: quinone oxidoreductase enhances proliferation inhibition by 4-hydroxytamoxifen.
The nonquinone compound, 4-OHT, was identified as a NQOR substrate as measured by reduction in the M7T assay. 4-OHT was then evaluated for effects on proliferation inhibition in two independent cell model systems, the MCF7 (NQO1+), MCF7 + dicoumarol (NQO1-) and the CHO (NQO1-) CHO-812 (NQO1+). NQOR activity predicts inhibition of proliferation by 4-OHT in these two models MCF7s were more sensitive to 4-OH tamoxifen with a PI50 of 2.65 nM than MCF-7 + dicoumarol with a PI50 of 1.84 microM (p<0.05, by one way ANOVA). CHO812s were also more sensitive to proliferation inhibition by 4-OH tamoxifen with a PI50 of 80.2 microM compared to the CHOs with a PI50 of 93.1 microM (p<0.05, by one-way ANOVA). Suggesting: 1) 4-OH tamoxifen is reduced by NQOR and 2) the reduced product is more active than the parent compound.
Allen
Peter G
PG
School of Pharmacy, University of Wisconsin-Madison, 53705-2222, USA.
Kolesar
Jill M
JM
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D016466:CHO Cells / Q000187:drug effects / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D001728:Dicumarol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D010084:Oxidation-Reduction; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D006131:Growth Inhibitors; D013629:Tamoxifen; C016601:afimoxifene; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone)