Aug 9, 2005

Inhibition of thioredoxin reductase but not of glutathione reductase by the major classes of alkylating and platinum-containing anticancer compounds

Free Radical Biology & Medicine
Anne-Barbara WitteE S Arnér

Abstract

Mammalian thioredoxin reductase (TrxR) is important for cell proliferation, antioxidant defense, and redox signaling. Together with glutathione reductase (GR) it is the main enzyme providing reducing equivalents to many cellular processes. GR and TrxR are flavoproteins of the same enzyme family, but only the latter is a selenoprotein. With the active site containing selenocysteine, TrxR may catalyze reduction of a wide range of substrates, but can at the same time easily be targeted by electrophilic compounds due to the extraordinarily high reactivity of a selenolate moiety. Here we addressed the inhibition of the enzyme by major anticancer alkylating agents and platinum-containing compounds and we compared it to that of GR. We confirmed prior studies suggesting that the nitrosourea carmustine can inhibit both GR and TrxR. We next found, however, that nitrogen mustards (chlorambucil and melphalan) and alkyl sulfonates (busulfan) efficiently inhibited TrxR while these compounds, surprisingly, did not inhibit GR. Inhibitions were concentration and time dependent and apparently irreversible. Anticancer anthracyclines (daunorubicin and doxorubicin) were, in contrast to the alkylating agents, not inhibitors but poor substrates of Tr...Continue Reading

  • References45
  • Citations112

References

  • References45
  • Citations112

Citations

Mentioned in this Paper

Doxorubicin
Nitrosoureas, antineoplastic alkylating agents
Platinum-containing Compounds [Chemical/Ingredient]
Nitrogen Mustard Compounds
Thioredoxin Reductase (NADPH)
Antineoplastic Agents
Exertion
Derivatives
Enzymes, antithrombotic
n-Butane-1,3-di(methylsulfonate)

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