Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246.

Scientific Reports
Lena HaffoArne Holmgren

Abstract

The tumor suppressor p53 is commonly inactivated in human tumors, allowing evasion of p53-dependent apoptosis and tumor progression. The small molecule APR-246 (PRIMA-1Met) can reactive mutant p53 in tumor cells and trigger cell death by apoptosis. The thioredoxin (Trx) and glutaredoxin (Grx) systems are important as antioxidants for maintaining cellular redox balance and providing electrons for thiol-dependent reactions like those catalyzed by ribonucleotide reductase and peroxiredoxins (Prxs). We show here that the Michael acceptor methylene quinuclidinone (MQ), the active form of APR-246, is a potent direct inhibitor of Trx1 and Grx1 by reacting with sulfhydryl groups in the enzymes. The inhibition of Trx1 and Grx1 by APR-246/MQ is reversible and the inhibitory efficiency is dependent on the presence of glutathione. APR-246/MQ also inhibits Trxs in mutant p53-expressing Saos-2 His-273 cells, showing modification of Trx1 and mitochondrial Trx2. Inhibition of the Trx and Grx systems leads to insufficient reducing power to deoxyribonucleotide production for DNA replication and repair and peroxiredoxin for removal of ROS. We also demonstrate that APR-246 and MQ inhibit ribonucleotide reductase (RNR) in vitro and in living cells....Continue Reading

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Citations

Mar 21, 2019·Journal of Molecular Cell Biology·Sofi E ErikssonKlas G Wiman
Jul 9, 2020·International Journal of Cancer. Journal International Du Cancer·Michael J Duffy, John Crown
Nov 14, 2019·International Journal of Molecular Sciences·Kamesh R Babu, Yvonne Tay
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Aug 4, 2020·Seminars in Cancer Biology·Michael J DuffyJohn Crown
May 2, 2021·Redox Biology·Fernando T OgataLucia Coppo
Sep 11, 2021·Life Sciences·Fabiola Lilí Sarmiento-SalinasPaola Maycotte
Jul 29, 2021·Molecular Cancer Therapeutics·Kenji M FujiharaNicholas J Clemons
Aug 28, 2021·Annual Review of Pharmacology and Toxicology·Radosveta Gencheva, Elias S J Arnér

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Methods Mentioned

BETA
ion exchange chromatography
protein assay

Software Mentioned

GraphPad
GraphPad Prism
Quantity One

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