Organoselenium Compounds Modulate Extracellular Redox by Induction of Extracellular Cysteine and Cell Surface Thioredoxin Reductase

Abstract

The effect of selenium compounds on extracellular redox modulating capacity was studied in murine macrophage RAW 264.7 cells and differentiated human THP-1 monocytes. The arylselenium compounds benzeneselenol (PhSeH), dibenzyl diselenide (DBDSe), diphenyl diselenide (DPDSe), and ebselen were capable of inducing extracellular cysteine accumulation via a cystine- and glucose-dependent process. Extracellular cysteine production was dose-dependently inhibited by glutamate, an inhibitor of cystine/glutamate antiporter (Xc(-) transporter), supporting the involvement of Xc(-) transporter for cystine uptake in the above process. These arylselenium compounds also induced cellular thioredoxin reductase (TrxR) expression, particularly at the exofacial surface of cells. TrxR1 knockdown using small interfering RNA attenuated TrxR increases and cysteine efflux induced in cells by DPDSe. Sodium selenite (Na2SeO3), selenomethionine (SeMet), seleno-l-cystine (SeCySS), and Se-methylselenocysteine (MeSeCys) did not have these effects on macrophages under the same treatment conditions. The effects of organoselenium compounds on extracellular redox may contribute to the known, but inadequately understood, biological effects of selenium compounds.

Reaction kinetics and targeting to cellular glutathione S-transferase of the glutathione peroxidase mimetic PhSeZnCl and its d,l-polylactide microparticle formulation

“…In fact, the characteristic reactivity of this and other forms of organic Se with cellular thiols and the stimulation of H 2 O 2- -generating pathways confirmed in this study represent major concerns, being the cause of severe “stressogenic” events reviewed in [15–17,40]. On the other hand, this chemistry can be a useful prerequisite in designing efficient redox catalysts for different chemical and biological destinies [7], as well as anticancer drugs with therapeutic applications in chemoresistant cancers, particularly those featuring an enhanced expression of GSH-related genes.…”

“…Mechanistic aspects of Se-organic compounds at the cellular level include redox modulation and stress response effects recently, reviewed in [15]. These compounds stimulate to different extents the generation of reactive oxygen species (ROS), depletion of intracellular GSH, and selected modifications of the thiol/disulfide status of signaling proteins, some of which act as redox sensors to coordinate the transcriptional response to electrophilic substances.…”

An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase

“…Both X-ray crystallography and MALDI-MS were used previously to show that several terpyridineplatinum(II) complexes bind to TrxR [22], while various gold complexes have also proven to be potent inhibitors of this enzyme [24][25][26]. In addition, TrxR is involved in the redox activity of RAW264.7 macrophages [54][55][56]. Our interest in examining the binding of gold complexes, and possibly Au NPs, to TrxR was derived in part from the contribution that these interactions may make to their anti-arthritic activity [18,19].…”

Dose Effect of Rhenium (I)-diselenoether as Anticancer Drug in Resistant Breast Tumor-bearing Mice After Repeated Administrations

“…The oxidation of cysteine, especially its thiol or thiolate groups, has been described as a major event involved in modifying the function of signaling proteins and cysteine redox post-translational modifications affect protein structure and function (34,35). On the other hand, organo-Se compounds modulate extracellular redox by induction of extracellular cysteine and cell-surface thioredoxin reductase (36). The administration of Se drugs may induce either oxidant or antioxidant effects in the cells (37)(38)(39) by oxidation or reduction of thiol-containing proteins, depending on the influence of neighboring groups and redox potential (31).…”