title: 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.
authors.affiliation: Synthesis Section, Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain. eisopena@alumni.unav.es
authors.forename: Elena
authors.initials: E
authors.lastname: Ibáñez
authors.forename: Mette
authors.initials: M
authors.lastname: Stoedter
authors.forename: Peter Josef
authors.initials: PJ
authors.lastname: Hofmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Plano
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
authors.forename: Paul A
authors.initials: PA
authors.lastname: Nguewa
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Palop
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanmartín
authors.forename: Lutz
authors.initials: L
authors.lastname: Schomburg
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D016566:Organoselenium Compounds / Q000737:chemistry* / Q000494:pharmacology*; D051149:Selenoprotein P / Q000378:metabolism; D051140:Selenoproteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D016566:Organoselenium Compounds; C487710:SELENOS protein, human; D051149:Selenoprotein P; D051140:Selenoproteins; D005979:Glutathione Peroxidase; D013880:Thioredoxin-Disulfide Reductase