Structure- and cell-specific effects of imidoselenocarbamates on selenoprotein expression and activity in liver cells in culture

Abstract

The essential micronutrient selenium (Se) exerts its biological effects mainly through selenoproteins thereby affecting a number of physiological pathways including intracellular redox control, stress response and cancer cell proliferation. Besides affecting selenoprotein expression, some selenocompounds have been synthesized and analyzed in order to serve as chemotherapeutic substances preferentially targeting cancer cells. This promising chemotherapeutic potential has recently been verified for a particular imidoselenocarbamate in a mouse tumor model. In the present study we tested the effects of this and a number of related Se-methyl- and Se-benzyl-imidoselenocarbamates on selenoprotein expression in nontransformed and hepatic carcinoma cells in culture. Most of the Se-benzyl-imidoselenocarbamates strongly stimulated selenoprotein P (SePP) secretion while the Se-methyl-imidoselenocarbamates elicited less pronounced effects in hepatocarcinoma HepG2 cells. However, most of the Se-methyl-imidoselenocarbamates increased glutathione peroxidase (GPx) activity and decreased thioredoxin reductase (TXNRD) activity in parallel, while the majority of the Se-benzyl-imidoselenocarbamates were without a respective effect in HepG2 cells. Performing inhibitor assays in vitro, GPx activity was unaffected by the imidoselenocarbamates. In contrast, most of the Se-methyl-imidoselenocarbamates inhibited TXNRD activity in vitro in line with the results in HepG2 cells. Both classes of imidoselenocarbamates strongly induced selenoprotein S (SELS) expression without a respective increase in ER stress or unfolded protein response which are known inducers of SELS biosynthesis. Notably, many of these effects were cancer cell-specific, and not observed in nontransformed AML12 hepatocytes. Our results indicate that these novel selenocompounds affect expression and activity of crucial selenoenzymes in a compound- and cell-specific way in hepatocytes. Especially the Se-methyl-imidoselenocarbamates elicit a unique spectrum of activities by stimulating GPx activity, SELS expression and SePP secretion while inhibiting TXNRD activity in hepatocarcinoma cells. These effects represent a promising finding with respect to the identification of therapeutic selenocompounds, as cancer-cell specificity is combined with desired effects on selenoprotein expression and activity.

Novel N,N′-Disubstituted Acylselenoureas as Potential Antioxidant and Cytotoxic Agents

“…During the implementation of our scientific program based in the synthesis and biological evaluation of Se compounds, we have synthetized and observed the antioxidant and anticancer activity of closely related imidoselenocarbamates [26][27][28][29][30][31][32][33][34], seleno-quinazoline, and pyrido [2,3-d]pyrimidine derivatives [33,[35][36][37]. Some evidence has pointed out that relatively simple selenoureas ( Figure 1A) might possess a superoxide radical scavenging activity accompanied by a low toxicity in human cells [38].…”

III. Ikergazte. Nazioarteko ikerketa euskaraz. Kongresuko artikulu bilduma. Osasun Zientziak

“…Taldean, aurrez sintetizatutako hainbat seleniodun molekulak aktibitate leishmanizida aurkeztu zuten. (9,11,12,13,17,19,21,22,23,26) Bestalde, organoseleno konposatu ezberdinak parasitemiaren murrizketa suertatzen dutela demostratua da. Are gehiago, arratoietan manifestazio klinikoak eta heriotza-tasa murrizten dute.…”

Novel quinazoline and pyrido[2,3-d]pyrimidine derivatives and their hydroselenite salts as antitumoral agents

“…Natural organic and inorganic sources of Se as well as synthetic organoselenium compounds have been shown to be effective and safe in the treatment and prevention of cancer. [23][24][25][26] The observations outlined above, along with our experience in the synthesis and antitumoral studies related to quinazoline and pyrido [2,3-d]pyrimidines, [27][28][29][30][31] so as a continuation with our efforts in the search of new selenium derivatives with antitumoral properties [32][33][34][35][36][37][38] enthused us to develop new 2,4-disubstituted quinazoline and pyrido [2,3-d]pyrimidine derivatives. The linkages investigated were (-NH-), which was inserted in positions 2 and/or 4, and sulfur which was introduced in the 2-position.…”