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NAD(P)H:Quinone Oxidoreductase-1-Dependent and -Independent Cytotoxicity of Potent Quinone Cdc25 Phosphatase Inhibitors

Han, Y and Shen, H and Carr, BI and Wipf, P and Lazo, JS and Pan, SS (2004) NAD(P)H:Quinone Oxidoreductase-1-Dependent and -Independent Cytotoxicity of Potent Quinone Cdc25 Phosphatase Inhibitors. Journal of Pharmacology and Experimental Therapeutics, 309 (1). 64 - 70. ISSN 0022-3565

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Abstract

Cdc25 dual-specificity phosphatases coordinate cell cycle progression and cellular signaling. Consequently, Cdc25 inhibitors represent potential anticancer agents. We evaluated >10,000 compounds for inhibition of human Cdc25 phosphatases and identified many potent and selective inhibitors, which all contained a quinone. Bioreductive enzymes frequently detoxify or activate quinones. Therefore, we evaluated the effect of NAD(P)H:quinone oxidoreductase-1 (NQO1) and reductase-rich microsomes on the activity of three quinone-containing Cdc25 inhibitors: 2-(2-hydroxyethylsulfanyl)-3-methyl-1,4-naphthoquinone (Cpd 5, compound 5; NSC 672121), 2,3-bis-(2-hydroxyethylsulfanyl)-1,4-naphthoquinone (NSC 95397), and 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione (NSC 663284). Each inhibitor was reduced by human NQO1 (Km of 0.3-0.5 μM) but none by microsomes. Compounds were evaluated with six cancer cell lines containing different amounts of NQO1: HT-29 (1056 nmol/mg/ min), HCT116 (660 nmol/mg/min), sublines HCT116-R30A (28 nmol/mg/min) and HCT-116R30A/NQ5 (934 nmol/mg/min), MDA-MB-231/Q2 (null NQO1), and subline MDA-MB-231/Q6 (124 nmol/mg/min) but containing similar amounts of microsomal cytochrome P450 reductase and cytochrome b5 reductase. Growth inhibition and G2/M arrest by Cpd 5 was proportional to NQO1 levels, requiring 4- to 5-fold more Cpd 5 to inhibit HCT-116 or HCT-116R30A/NQ5 compared with HCT-116R30A. In contrast, in all tested cell lines irrespective of NQO1 level, growth inhibition and G2/M arrest by NSC 95375 and NSC 663284 were similar (average IC50 of 1.3 ± 0.3 and 2.6 ± 0.4 μM, respectively). NSC 95375 and NSC 663284 also caused similar Cdk1 hyperphosphorylation, indicating similar Cdc25 inhibition. However, lower Cpd 5 concentrations were needed to produce Cdk1 hyperphosphorylation in sublines with minimal NQO1. Thus, NQO1 detoxified Cpd 5, probably by reducing it to a less active hydroquinone, whereas NSC 95397- and NSC 663284-generated cytotoxicity was unaffected by NQO1.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Han, Y
Shen, Hhos1@pitt.eduHOS1
Carr, BI
Wipf, Ppwipf@pitt.eduPWIPF
Lazo, JS
Pan, SS
Date: 1 April 2004
Date Type: Publication
Journal or Publication Title: Journal of Pharmacology and Experimental Therapeutics
Volume: 309
Number: 1
Page Range: 64 - 70
DOI or Unique Handle: 10.1124/jpet.103.059477
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-3565
MeSH Headings: CDC2 Protein Kinase--metabolism; Cell Division--drug effects; Cell Fractionation; Cell Line; Dicumarol--pharmacology; G2 Phase--drug effects; HT29 Cells; Humans; Microsomes--metabolism; Mitosis--drug effects; NAD(P)H Dehydrogenase (Quinone)--metabolism; NAD(P)H Dehydrogenase (Quinone)--physiology; Naphthoquinones--pharmacology; Phosphorylation; Quinolones--pharmacology; Quinones--pharmacology; Recombinant Proteins--metabolism; Tumor Cells, Cultured; cdc25 Phosphatases--antagonists & inhibitors
PubMed ID: 14718602
Date Deposited: 30 Jan 2014 18:20
Last Modified: 02 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/20431

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