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

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Lu J, Chew EH, Holmgren A

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

Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12288-93. Epub 2007 Jul 18.

PubMed ID

17640917 [ View in PubMed

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Abstract

Arsenic trioxide (ATO) is an effective cancer therapeutic drug for acute promyelocytic leukemia and has potential anticancer activity against a wide range of solid tumors. ATO exerts its effect mainly through elevated oxidative stress, but the exact molecular mechanism remains elusive. The thioredoxin (Trx) system comprising NADPH, thioredoxin reductase (TrxR), and Trx and the glutathione (GSH) system composed of NADPH, glutathione reductase, and GSH supported by glutaredoxin are the two electron donor systems that control cellular proliferation, viability, and apoptosis. Recently, the selenocysteine-dependent TrxR enzyme has emerged as an important molecular target for anticancer drug development. Here, we have discovered that ATO irreversibly inhibits mammalian TrxR with an IC(50) of 0.25 microM. Both the N-terminal redox-active dithiol and the C-terminal selenothiol-active site of reduced TrxR may participate in the reaction with ATO. The inhibition of MCF-7 cell growth by ATO was correlated with irreversible inactivation of TrxR, which subsequently led to Trx oxidation. Furthermore, the inhibition of TrxR by ATO was attenuated by GSH, and GSH depletion by buthionine sulfoximine enhanced ATO-induced cell death. These results strongly suggest that the ATO anticancer activity is by means of a Trx system-mediated apoptosis. Blocking cancer cell DNA replication and repair and induction of oxidative stress by the inhibition of both Trx and GSH systems are suggested as cancer chemotherapeutic strategies.

DrugBank Data that Cites this Article

Drugs

Arsenic trioxide

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Arsenic trioxide	Thioredoxin reductase 1, cytoplasmic	Protein	Humans	Yes	Inhibitor	Details
Glutathione	Glutaredoxin-1	Protein	Humans	Unknown	Not Available	Details