Noble metal targeting of thioredoxin reductase - covalent complexes with thioredoxin and thioredoxin-related protein of 14 kDa triggered by cisplatin

Palladium (Pd) platinum (Pt) and gold (Au) are noble metals two of which have established medical use Pt has anticancer efficacy predominantly as cisplatin whereas the gold compound auranofin is used against arthritis Both compounds inhibit the selenoprotein thioredoxin reductase (TrxR) but Pd has not been studied in this regard Using salts of Pd Pt and Au as well as cisplatin and auranofin we found that Pd and Au were strikingly more potent inhibitors of recombinant TrxR1 than Pt The TrxR related nonselenoprotem glutathione reductase in pure form (but less so in a cellular context) as well as cellular thioredoxin (Trx) activitie were inhibited by the gold salt KAuCl4 but were little affected by auranofin or the other compounds In an analysis of three cancer cell lines the extent of inhibition of TrxR activity and decrease in cell viability depended upon the choice of both noble metal and ligand and also seemed independent of p53 status During treatment of cells with cisplatin covalent complexes of TrxR1 with either Trx1 or TRP14 (Trx related protein of 14 kD i) were formed as verified by Western blot analyses and mass spectrometry These results reveal that Au and Id are strong inhibitors of TrxR but Pt and cisplatin trigger highly specific cellular effects on the Trx system including covalent cross linking of TrxR1 with Trx1 and TRP14 (C) 2010 Elsevier Inc All rights reserved