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

Lena Haffo1,2, Jun Lu1,3, Vladimir J N Bykov2

  • 1Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.

Scientific Reports
|August 25, 2018
PubMed

Insights

The cancer drug APR-246 reactivates mutant p53 and inhibits key antioxidant systems, leading to tumor cell death. This dual action offers a novel cancer therapy strategy by disrupting redox balance and promoting apoptosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Tumor suppressor p53 is frequently inactivated in human cancers, promoting tumor progression by evading apoptosis.
  • APR-246 (PRIMA-1Met) is a small molecule that can reactivate mutant p53, inducing apoptosis in tumor cells.
  • Thioredoxin (Trx) and glutaredoxin (Grx) systems are crucial cellular antioxidants involved in redox balance and thiol-dependent reactions.

Purpose of the Study:

  • To investigate the mechanism of action of APR-246, specifically its active form methylene quinuclidinone (MQ).
  • To determine if APR-246/MQ inhibits the Trx and Grx systems and affects deoxyribonucleotide production and reactive oxygen species (ROS) removal.
  • To explore the combined effect of mutant p53 reactivation and redox system inhibition by APR-246 in cancer therapy.

Main Methods:

  • Investigated the direct inhibition of Trx1 and Grx1 by APR-246/MQ in vitro.
  • Assessed the effect of APR-246/MQ on Trx systems in mutant p53-expressing Saos-2 cells.
  • Examined the impact of APR-246/MQ on deoxyribonucleotide production, ROS removal, and ribonucleotide reductase (RNR) activity.
  • Evaluated the reversibility of APR-246/MQ inhibition and its dependence on glutathione.

Main Results:

  • APR-246/MQ directly and reversibly inhibits Trx1 and Grx1 by reacting with their sulfhydryl groups, with efficiency dependent on glutathione.
  • APR-246/MQ inhibits Trx1 and Trx2 in mutant p53-expressing cells, leading to impaired DNA replication/repair and ROS detoxification.
  • APR-246 and MQ were shown to inhibit ribonucleotide reductase (RNR) both in vitro and in living cells.

Conclusions:

  • APR-246/MQ acts as a potent inhibitor of cellular thiol-dependent redox systems, including Trx and Grx.
  • The inhibition of these redox systems by APR-246/MQ disrupts essential cellular processes like DNA synthesis and ROS management.
  • APR-246 induces tumor cell death via dual mechanisms: reactivation of mutant p53 and inhibition of critical redox pathways, presenting a novel cancer therapeutic strategy.

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