APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase
Open accessAbstract
The low-molecular-weight compound APR-246 (PRIMA-1(MET)) restores wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells. We show here that APR-246 also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance. APR-246 inhibited both recombinant TrxR1 in vitro and TrxR1 in cells. A Sec-to-Cys mutant of TrxR1 was not inhibited by APR-246, suggesting targeting of the selenocysteine residue in wild-type TrxR1. Preheated APR-246 and its conversion product methylene quinuclidinone (MQ) were much more efficient TrxR1 inhibitors than APR-246 itself, indicating that MQ is the active compound responsible for TrxR1 enzyme inhibition. TrxR1 inhibited by MQ was still functional as a pro-oxidant NADPH oxidase. Knockdown of TrxR1 caused a partial and reproducible attenuation of APR-246-induced 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 affect cellular redox status via targeting of TrxR1. Our findings provide an explanation for the previously observed effects of APR-246 on tumor cells lacking mutant p53.
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Eprenetapopt increases oxidative stress by depletion of glutathione and inhibition of thioredoxin reductase, leading to accumulation of reactive oxygen species and further promoting tumor cell death.
“In addition, eprenetapopt increases oxidative stress by depletion of glutathione and inhibition of thioredoxin reductase, leading to accumulation of reactive oxygen species and further promoting tumor cell death.22,23”
From Eprenetapopt (APR-246) and Azacitidine in <i>TP53</i> -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [23]
The Results section ('TrxR1 knockdown protects tumor cells against APR-246-induced cell death and ROS'; page unavailable) reports that APR-246 increased oxidation in the tested tumor cells and that TrxR1 knockdown attenuated the induced ROS. The Discussion links TrxR1 targeting to APR-246-induced cell death, but the passages do not show that APR-246 depletes glutathione. (LLM, conf=0.88)
Experimental — accuracy not yet measuredChanges in Trx redox status correlate with induction of cell death in Saos-2 and Saos-2-His-273 cells, as previously described.
“These changes of Trx redox status correlate with induction of cell death in Saos-2 and Saos-2-His-273 cells, as previously described15.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [15]
The Results section on TrxR inhibition in cells reports reduced thioredoxin reductase activity in Saos-2 and Saos-2-His273 cells after APR-246 treatment. A separate Results section links APR-246-induced oxidation and cell death in H1299 cell lines, not the Saos-2 lines. The copy therefore does not establish the claimed correlation between thioredoxin (Trx) redox status and cell death in Saos-2 and Saos-2-His273 cells; no page numbers are provided. (LLM, conf=0.82)
Experimental — accuracy not yet measuredTrxR is inactivated by MQ and converted to an NADPH oxidase that produces ROS.
“However, TrxR is inactivated by MQ and converted to an NADPH oxidase that produces ROS15.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [15]
The Results report that MQ inhibits TrxR1’s thioredoxin-reducing activity while leaving its NADPH oxidase activity largely intact. The Discussion proposes that MQ-modified TrxR1 can act as a dedicated NADPH oxidase and directly induce ROS, but presents that conversion and its ROS contribution as a mechanism rather than a directly established outcome. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAPR-246/MQ inhibits thioredoxin reductase (TrxR) in vitro and in living cells.
“APR-246/MQ has also been shown to inhibit thioredoxin reductase (TrxR) in vitro and in living cells15.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [15]
APR-246 may also act in the same manner as Michael acceptor drugs.
“APR-246 may also act in the same manner15.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [15]
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- Authors
- Peng, X., Zhang, M.-Q.-Z., Conserva, F., Hosny, G., Selivanova, G., Bykov, V. J. N., Arnér, E. S. J., & Wiman, K. G.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Arnér, E S J
- Wiman, K G
- Venue
- Cell Death & Disease
- Published
- 2013-10-24
- Volume
- 4
- Issue
- 10
- Pages
- e881-e881
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC3920950
- OpenAlex
- W4248347759
- Cited by
- 170
- References
- 50
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 13 · 2023: 16 · 2022: 15 · 2021: 24 · 2020: 12 · 2019: 15 · 2018: 19 · 2017: 10 · 2016: 15 · 2015: 8 · 2014: 5 · 2013: 1
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-04-13)
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Funders
- Cancerfonden
- Karolinska Institutet
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Organoselenium and organotellurium chemistry
- Keywords
- APR-246, thioredoxin reductase 1, selenocysteine, NADPH oxidase, redox homeostasis
- MeSH terms
- Animals, Cell Survival, Humans, Quinuclidines, Cell Death, Reactive Oxygen Species, NADPH Oxidases, Cytoprotection, RNA, Small Interfering, Cell Line, Tumor, Rats, Thioredoxin Reductase 1, Gene Knockdown Techniques
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