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OPENCitation: Cell Death and Disease (2013) 4, e881; doi:10.1038/cddis.2013.417 2013 Macmillan Publishers Limited All rights reserved 2041-4889/www.nature/cddisAPR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a committed NADPH oxidaseX Peng1,4, M-Q-Z Zhang2,4, F Conserva2,4, G Hosny2, G Selivanova3, VJN Bykov2, ESJ Arner*,1 and KG Wiman*,The low-molecular-weight compound APR-246 (PRIMA-1MET) restores wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells.Vildagliptin We show here that APR-246 also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a important regulator of cellular redox balance. APR-246 inhibited each recombinant TrxR1 in vitro and TrxR1 in cells. A Sec-to-Cys mutant of TrxR1 was not inhibited by APR-246, suggesting targeting in the selenocysteine residue in wild-type TrxR1. Preheated APR-246 and its conversion product methylene quinuclidinone (MQ) were much far more effective TrxR1 inhibitors than APR-246 itself, indicating that MQ would be the active compound accountable for TrxR1 enzyme inhibition.Vorasidenib TrxR1 inhibited by MQ was nevertheless functional as a pro-oxidant NADPH oxidase.PMID:27108903 Knockdown of TrxR1 brought on a partial and reproducible attenuation of APR-246induced tumor cell death independently of p53 status. Cellular TrxR1 activity was also inhibited by APR-246 irrespective of p53 status. We show that APR-246 can directly have an effect on cellular redox status by means of targeting of TrxR1. Our findings provide an explanation for the previously observed effects of APR-246 on tumor cells lacking mutant p53. Cell Death and Disease (2013) four, e881; doi:ten.1038/cddis.2013.417; published on the internet 24 OctoberSubject Category: CancerThe tumor suppressor p53 is often inactivated by missense or nonsense mutations in human tumors,1 enabling tumor cell survival and progression to more malignant variants. Additionally, p53 mutation is among the major causes behind resistance to chemotherapy and radiotherapy.four,five Restoration of wild-type p53 function triggers speedy tumor regression in vivo.six For that reason, mutant p.