Synthesis Section, Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea, 1, E-31008 Pamplona, Spain.
Metallomics. 2012 Dec;4(12):1297-307. doi: 10.1039/c2mt20096a.
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.
必需微量元素硒（Se）主要通过硒蛋白发挥其生物学作用，从而影响包括细胞内氧化还原控制、应激反应和癌细胞增殖在内的许多生理途径。除了影响硒蛋白的表达外，还合成和分析了一些硒化合物，以作为优先靶向癌细胞的化疗物质。这种有前途的化疗潜力最近在一个小鼠肿瘤模型中得到了一种特定的亚氨基硒代氨基甲酸酯的验证。在本研究中，我们测试了这种和一些相关的 Se-甲基-和 Se-苄基亚氨基硒代氨基甲酸酯对非转化和肝癌细胞系中硒蛋白表达的影响。大多数 Se-苄基亚氨基硒代氨基甲酸酯强烈刺激硒蛋白 P（SePP）的分泌，而 Se-甲基-亚氨基硒代氨基甲酸酯在肝癌 HepG2 细胞中则产生不太明显的作用。然而，大多数 Se-甲基-亚氨基硒代氨基甲酸酯平行增加谷胱甘肽过氧化物酶（GPx）活性并降低硫氧还蛋白还原酶（TXNRD）活性，而大多数 Se-苄基亚氨基硒代氨基甲酸酯在 HepG2 细胞中没有相应的作用。在体外进行抑制剂测定时，亚氨基硒代氨基甲酸酯对 GPx 活性没有影响。相反，大多数 Se-甲基-亚氨基硒代氨基甲酸酯在体外抑制 TXNRD 活性，与 HepG2 细胞中的结果一致。这两类亚氨基硒代氨基甲酸酯强烈诱导硒蛋白 S（SELS）的表达，而不会相应增加内质网应激或未折叠蛋白反应，这些都是 SELS 生物合成的已知诱导剂。值得注意的是，这些作用中的许多是癌细胞特异性的，在非转化的 AML12 肝细胞中观察不到。我们的结果表明，这些新型硒化合物以化合物和细胞特异性的方式影响肝细胞中关键硒酶的表达和活性。特别是 Se-甲基-亚氨基硒代氨基甲酸酯通过刺激 GPx 活性、SELS 表达和 SePP 分泌，同时抑制肝癌细胞中 TXNRD 活性，产生独特的活性谱。这些作用在鉴定治疗性硒化合物方面代表了一个有希望的发现，因为癌细胞特异性与对硒蛋白表达和活性的期望作用相结合。
