کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10739280 | 1046869 | 2005 | 8 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Inhibition of thioredoxin reductase but not of glutathione reductase by the major classes of alkylating and platinum-containing anticancer compounds
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کلمات کلیدی
DTNBBCNUTrxR5,5′-dithiobis(2-nitrobenzoic acid) - 5،5'-dithiobis (2-nitrobenzoic acid)BSA - BSAbovine serum albumin - آلبومین سرم گاوOxaliplatin - اگزالی پلاتینthioredoxin reductase - تریودوکسین ردوکتازDaunorubicin - داونوروبیسینDoxorubicin - دوکسوروبیسینSelenocysteine - سلنوسیستینSelenoprotein - سلنوپروتئینcisplatin - سیس پلاتینAlkylating agents - عوامل آلکیل کردنglutathione reductase - گلوتاتیون ردوکتاز
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Free Radical Biology and Medicine - Volume 39, Issue 5, 1 September 2005, Pages 696-703
Journal: Free Radical Biology and Medicine - Volume 39, Issue 5, 1 September 2005, Pages 696-703
نویسندگان
Anne-Barbara Witte, Karin AnestÃ¥l, Elin Jerremalm, Hans Ehrsson, Elias S.J. Arnér,