Organo-diselenides are well documented for pro-oxidant effects in tumor cells. However, the present study demonstrated that 2,2′-dipyridyl diselenide (Py₂Se₂) induced cytotoxicity in human non-small cell lung carcinoma (A549) cells through reductive stress marked by a significant decrease in the basal level of reactive oxygen species and a concurrent decrease in the ratio of oxidised (GSSG) and reduced (GSH) glutathione. The IC₅₀ (concentration inducing 50% cytotoxicity) of Py₂Se₂ in A549 and human normal lung fibroblast (WI38) cells was ∼8.5 μM and ∼5.5 μM, respectively, indicating that Py₂Se₂ did not exhibit selective toxicity towards cancer cells. Cell free studies indicated that Py₂Se₂ acted as a substrate of thioredoxin reductase (TrxR) and accordingly it was proposed that TrxR mediated reduction of Py₂Se₂ within cells might be generating intermediates leading to a reductive environment. Despite generating a reducing environment, Py₂Se₂ caused significant DNA damage, G1 phase arrest and apoptosis. The mechanistic investigation revealed that Py₂Se₂ induced G1 arrest was mediated through up-regulation of p21 transcript in a p53 independent manner. Further, the apoptotic effect of Py₂Se₂ was associated with the increase in the levels of unfolded protein response markers like BiP and CHOP, mitochondrial permeability (JC1) and apoptotic markers such as cleaved caspase-3 and poly (ADP-ribose) polymerase. Finally, pre-treatment with N-acetylcysteine (a stimulator of GSH biosynthesis) or L-buthionine sulfoximine (an inhibitor of GSH biosynthesis) increased and decreased the Py₂Se₂ mediated apoptosis, respectively. This confirmed that the cytotoxicity of Py₂Se₂ in A549 cells was triggered through reductive stress.

中文翻译：

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2,2'-联吡啶二硒化物 (Py2Se2) 通过清除 ROS 和减少应激诱导人肺癌 (A549) 细胞的 G1 期阻滞和细胞凋亡。

有机二硒化物在肿瘤细胞中具有促氧化作用。然而，本研究表明，2,2'-联吡啶二硒化物 ( Py ₂ Se ₂ ) 通过还原性应激诱导人非小细胞肺癌 (A549) 细胞的细胞毒性，其特征是活性氧的基础水平显着降低氧化型 (GSSG) 和还原型 (GSH) 谷胱甘肽的比例同时降低。Py ₂ Se ₂在 A549 和人正常肺成纤维细胞 (WI38) 细胞中的 IC ₅₀（浓度诱导 50% 细胞毒性）分别为 ~8.5 μM 和 ~5.5 μM，表明Py ₂ Se ₂对癌细胞没有表现出选择性毒性。无细胞研究表明Py ₂ Se ₂充当硫氧还蛋白还原酶 (TrxR) 的底物，因此有人提出 TrxR 介导的细胞内Py ₂ Se ₂的还原可能会产生导致还原环境的中间体。尽管产生了还原环境，但Py ₂ Se ₂引起了显着的 DNA 损伤、G1 期停滞和细胞凋亡。机理研究表明，Py ₂ Se ₂诱导的 G1 期阻滞是通过以 p53 独立方式上调 p21 转录物介导的。此外，Py ₂ Se ₂的凋亡作用与未折叠蛋白反应标志物（如 BiP 和 CHOP）、线粒体通透性 (JC1) 和凋亡标志物（如裂解的 caspase-3 和聚（ADP-核糖）聚合酶）水平的增加有关。 . 最后，用N-乙酰半胱氨酸（一种 GSH 生物合成的刺激剂）或L-丁硫氨酸亚砜亚胺（一种 GSH 生物合成的抑制剂）预处理分别增加和减少了Py ₂ Se ₂介导的细胞凋亡。这证实了Py ₂ Se的细胞毒性A549 细胞中的₂是通过还原性压力触发的。