Thioredoxin reductases inhibition

Rigobello MP, Scutari G, Folda A, Bindoli A (2004) Mitochondrial thioredoxin reductase inhibition by gold(I) compounds and concurrent stimulation of permeability transition and release of cytochrome c. Biochem Pharmacol 67 689-696... 

Vergara E, Casini A, Sorrentino F et al (2010) Anticancer therapeutics that target selenoenzymes synthesis, characterization, in vitro cytotoxicity, and thioredoxin reductase inhibition of a series of gold(l) complexes containing hydrophilic phosphine ligands. Chem Med Chem 5 96-102... 

Nordberg J et ai Mammalian thioredoxin reductase is irreversibly inhibited by dinitrohaiobenzenes by alkylation of both the redox active selenocysteine and its neighboring cysteine residue.) Biol Chem 1998 273 10835. 

PiaRigobello, M., Messori, L., Marcon, G., Cinellu, M.A., Bragadin, M., Folda, A., Scutari, G. and Bindoli, A. (2004) Gold complexes inhibit mitochondrial thioredoxin reductase consequences on mitochondrial functions. Journal of Inorganic Biochemistry, 98, 1634—1641. 

An additional topic for anticancer research involving organotellnrium compounds was thioredoxin reductase. Since in several human cancers thioredoxin expression is increased, several organotellurium compounds have been tested. 4,4 -Disubstituted dior-ganyl tellurides have been shown to be effective inhibitors of thioredoxin reductase and also to inhibit the growth of human cells in culture. ... 

Finally the analogue of vitamin shows interesting inhibition characteristics towards thioredoxin reductase. 

NF-kB inhibition. Aqueous extract of mainstream smoke (smoke-bubbled phosphate-buffered saline), in Swiss 3T3 cells, decreased DNA binding of NF-kB during the first 2 hours of exposure and increased more than twofold over controls after 4-6 hours of exposure. There was lack of phosphorylation and degradation of iKB-a and a significant increase in thioredoxin reductase mRNA after 2-6 hours of exposure. Results indicated that the activity of NF-kB in smoke-treated cells was subject mainly to a redox-controlled mechanism dependent on the availability of reduced thioredoxin rather than being controlled by its normal regulator, iKB-a " ". 

In the search for possible targets the inhibition activity of a range of RAPTA compounds was studied for two specific enzymes - namely thioredoxin reductases (TrxR) and cathepsin B (cat B), important targets in cancer chemotherapy [28]. TrxR was chosen as it is highly relevant with respect to gold-based drugs (see below) and cat B is implicated in various stages of metastasis which correlate to the observed in vitro effects of RAPTA-T [29], It turned out that while the selected compounds (Fig. 3) are not inhibitors of TrxR with the exception of carboRAPTA-C, they are active inhibitors of cat B [28],... 

Witte AB, Anestal K, Jerremalm E, Ehrsson H, Amer ES (2005) Inhibition of thioredoxin reductase but not of glutathione reductase by the major classes of alkylating and platinum-containing anticancer compounds. Free Radic Biol Med 39 696-703... 

Omata Y, Folan M, Shaw M, Messer RL, Lockwood PE, Hobbs D, Bouillaguet S, Sano H, Lewis JB, Wataha JC (2006) Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin reductase (TrxRl). Toxicol In Vitro 20 882-890... 

Gromer S Arscott, LD WCH, Jr SRH, Becker K (1998) Human placenta thioredoxin reductase. Isolation of the selenoenzyme, steady state kinetics, and inhibition by therapeutic gold compounds. J Biol Chem 273 20096-20101... 

Glutaredoxin is another small ubiquitous protein with a different dithiol-active center which catalyzes GSH-disulfide transhydrogenase reactions. It is GSH-specific and cannot be reduced by thioredoxin reductase. It uses GSH and an NADPH-coupled glutaredoxin reductase to catalyze the reduction of a variety of disulfide substrates, including 2-hydroxyethyl-disulfide and ribonucleotide reductase [281]. Since GSSG inhibits the latter reaction, a high ratio of GSH to GSSG will promote the synthesis of deoxyribonucleotides, which is a likely control mechanism of DNA synthesis. 

GSH reductase (Styblo et ah, 1997) and thioredoxin reductase (Lin eta/., 1999). The inhibition may be due to the interaction of trivalent arsenic with critical thiol groups in these molecules. A mechanism of toxicity of pentavalent inorganic arsenic, such as arsenate, is its reduction to a trivalent form, such as arsenite. The reduction of arsenate to arsenite occurs in vivo. Another potential mechanism is the replacement of phosphate with arsenate. 

The diaryl telluride, alkyl aryl telluride, and dialkyl telluride carrying sulfopropyl groups were prepared and were found to be the most efficient tellurium based inhibitors of thioredoxin reductase ever tested. The results clearly showed that of the four cyclic aryl alkyl chalcogenides 162-165, all primitive analogues of vitamin E, only the tellurium compound, 165, showed interesting inhibition characteristics. 

Thioredoxin reductases have also been purified from yeast (43, 134) and from rat fiver (135). Thioredoxin reductase from yeast is a flavo-protein with a molecular weight of approximately 75,000 and consists of two subunits, each containing one molecule of FAD. Although the amino acid composition of this thioredoxin reductase is quite different from that of E. coli, both enzymes contain 5 half-cystine residues and have almost identical absorption spectra. Like the E. coli enzyme, thioredoxin reductase from yeast is completely inhibited by p-chloro-mercuriphenylsulfonate (PCMS) only in the presence of NADPH suggesting that the yeast enzyme also contains a disulfide bridge at the catalytic site. 

S Lin, LM Del Razo, M Styblo, C Wang, WR Cullen, DJ Thomas. Arsenicals inhibit thioredoxin reductase in cultured rat hepatocytes. Chem Res Toxicol 14 ... 

T-1 is reduced by NADPH and the flavoprotein thioredoxin reductase from E. coli. T-2 is not reduced by the bacterial reductase, nor does it inhibit reduction of T-1 in a mixed system, indicating that it does not bind to the E. coli protein. 

Evidence suggests that inhibition of thioredoxin reductase (TrxR), a seleno-enzyme critically involved in the regulation of the intracellular redox state and of mitochondrial functions [20], could be highly relevant. In fact, inhibition of TrxR by gold compounds results in the opening of the mitochondrial pore leading to the release of cytochrome c and ultimately inducing apoptosis [21]. 

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