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Elucidation of Thioredoxin as a Molecular Target for Antitumor Quinols

¹ Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, United Kingdom and ² Science Applications International Co.-Frederick, Inc., Screening Technologies Branch, Laboratory of Functional Genomics, National Cancer Institute, Frederick, Maryland

Requests for reprints: Tracey D. Bradshaw, Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, United Kingdom. Phone: 44-115-951-3419; Fax: 44-115-951-3412; E-mail: tracey.bradshaw{at}nottingham.ac.uk.

Heteroaromatic quinols 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1) and 4-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (2) exhibit potent and selective antitumor activity against colon, renal, and breast carcinoma cell lines in vitro (GI₅₀ < 500 nmol/L). In vivo growth inhibition of renal, colon, and breast xenografts has been observed. Profound G₂-M cell cycle block accompanied down-regulation of cdk1 gene transcription was corroborated by decreased CDK1 protein expression following treatment of HCT 116 cells with growth inhibitory concentrations of 1 or 2. The chemical structure of the quinol pharmacophore 4-(hydroxycyclohexa-2,5-dienone) suggested that these novel agents would readily react with nucleophiles in a double Michael (ß-carbon) addition. Indeed, COMPARE analysis within the National Cancer Institute database revealed a number of chemically related quinone derivatives that could potentially react with sulfur nucleophiles in a similar manner and suggested that thioredoxin/thioredoxin reductase signal transduction could be a putative target. Molecular modeling predicted covalent irreversible binding between quinol analogues and cysteine residues 32 and 35 of thioredoxin, thereby inhibiting enzyme activity. Binding has been confirmed, via mass spectrometry, between reduced human thioredoxin and 1. Microarray analyses of untreated HCT 116 cells and those exposed to either 1 (1 µmol/L) or 2 (500 nmol/L and 1 µmol/L) determined that of 10,000 cancer-related genes, expression of thioredoxin reductase was up-regulated >3-fold. Furthermore, quinols 1 and 2 inhibited insulin reduction, catalyzed by thioredoxin/thioredoxin reductase signaling in a dose-dependent manner (IC₅₀ < 6 µmol/L). Results are consistent with a mechanism of action of novel antitumor quinols involving inhibition of the small redox protein thioredoxin.

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