title: Inhibition of thioredoxin reductase but not of glutathione reductase by the major classes of alkylating and platinum-containing anticancer compounds.
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 TrxR. We also found that TrxR, but not GR, was efficiently inhibited by both cisplatin, its monohydrated complex, and oxaliplatin. Carboplatin, in contrast, could not inhibit any of the two enzymes. These findings lead us to conclude that representative compounds of the major classes of clinically used anticancer alkylating agents and most platinum compounds may easily target TrxR, but not GR. The TrxR inhibition should thereby be considered as a factor that may contribute to the cytotoxicity seen upon clinical use of these drugs.
authors.affiliation: Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Anne-Barbara
authors.initials: AB
authors.lastname: Witte
authors.forename: Karin
authors.initials: K
authors.lastname: Anestål
authors.forename: Elin
authors.initials: E
authors.lastname: Jerremalm
authors.forename: Hans
authors.initials: H
authors.lastname: Ehrsson
authors.forename: Elias S J
authors.initials: ES
authors.lastname: Arnér
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D001665:Binding Sites; D002066:Busulfan / Q000494:pharmacology; D002699:Chlorambucil / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors*; D008558:Melphalan / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D051381:Rats; D013053:Spectrophotometry / Q000379:methods; D013379:Substrate Specificity; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000975:Antioxidants; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002699:Chlorambucil; D004317:Doxorubicin; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; D002066:Busulfan; D002945:Cisplatin; D008558:Melphalan; D003630:Daunorubicin