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Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide

Jun Lu1, Eng-Hui Chew, Arne Holmgren

  • 1Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-17177 Stockholm, Sweden.

Proceedings of the National Academy of Sciences of the United States of America
|July 21, 2007
PubMed

Insights

Arsenic trioxide (ATO) cancer treatment works by inhibiting the thioredoxin reductase (TrxR) enzyme. This leads to oxidative stress and apoptosis, suggesting a new therapeutic strategy for solid tumors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Arsenic trioxide (ATO) is a known cancer therapeutic for acute promyelocytic leukemia with potential against solid tumors.
  • The precise molecular mechanisms underlying ATO's anticancer effects, particularly concerning oxidative stress, are not fully understood.
  • The thioredoxin (Trx) and glutathione (GSH) systems are critical for cellular proliferation, viability, and apoptosis, with TrxR being a key target for anticancer drug development.

Purpose of the Study:

  • To investigate the molecular mechanism of arsenic trioxide (ATO) in cancer treatment.
  • To determine if ATO targets the thioredoxin reductase (TrxR) enzyme.
  • To elucidate the role of the Trx system in ATO-induced cancer cell death.

Main Methods:

  • Assessing the inhibitory effect of ATO on mammalian TrxR enzyme activity in vitro.
  • Correlating MCF-7 cell growth inhibition with TrxR inactivation and Trx oxidation.
  • Evaluating the impact of glutathione (GSH) levels on ATO's efficacy and ATO-induced cell death.

Main Results:

  • Arsenic trioxide (ATO) irreversibly inhibits mammalian TrxR with an IC50 of 0.25 microM.
  • ATO's inhibition of TrxR leads to Trx oxidation and correlates with reduced cancer cell growth.
  • GSH attenuates ATO's inhibition of TrxR, while GSH depletion enhances ATO-induced cell death.

Conclusions:

  • ATO exerts its anticancer activity by irreversibly inhibiting TrxR, leading to Trx system-mediated apoptosis.
  • Blocking DNA replication and repair, alongside inducing oxidative stress via inhibition of Trx and GSH systems, represents a potential cancer chemotherapeutic strategy.

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