Lymphoma is a blood cancer comprising various subtypes. Although effective therapies are available, some patients fail to respond to treatment and can suffer from side effects. Antioxidant systems, especially the thioredoxin (Trx) and glutathione (GSH) systems, are known to enhance cancer cell survival, with thioredoxin reductase (TrxR) recently reported as a potential anticancer target. Since the GSH system can compensate for some Trx system functions, we investigated its response in three lymphoma cell lines after inhibiting TrxR activity with [Au(d2pype)2]Cl, a known TrxR inhibitor. [Au(d2pype)2]Cl increased intracellular reactive oxygen species (ROS) levels and induced caspase-3 activity leading to cell apoptosis through inhibiting both TrxR and glutathione peroxidase (Gpx) activity. Expression of the tumour suppresser gene TXNIP increased, while GPX1 and GPX4 expression, which are related to poor prognosis of lymphoma patients, decreased. Unlike SUDHL2 and SUDHL4 cells, which exhibited a decreased GSH/GSSG ratio after treatment, in KMH2 cells the ratio remained unchanged, while glutathione reductase and glutaredoxin expression increased. Since KMH2 cells were less sensitive to treatment with [Au(d2pype)2]Cl, the GSH system may play a role in protecting cells from apoptosis after TrxR inhibition. Overall, our study demonstrates that inhibition of TrxR represents a valid therapeutic approach for lymphoma.

中文翻译：

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研究[Au（d2pype）2] CL处理后淋巴瘤细胞中硫氧还蛋白和谷胱甘肽系统的反应

淋巴瘤是包括各种亚型的血液癌。尽管可以使用有效的疗法，但有些患者对治疗无反应，并可能出现副作用。已知抗氧化剂系统，尤其是硫氧还蛋白（Trx）和谷胱甘肽（GSH）系统可增强癌细胞的存活率，最近有报道称硫氧还蛋白还原酶（TrxR）是潜在的抗癌靶标。由于GSH系统可以补偿Trx系统的某些功能，因此我们在用已知的TrxR抑制剂[Au（d2pype）2] Cl抑制TrxR活性后，在三种淋巴瘤细胞系中研究了其应答。[Au（d2pype）2] Cl通过抑制TrxR和谷胱甘肽过氧化物酶（Gpx）的活性来增加细胞内活性氧（ROS）的水平并诱导caspase-3活性，从而导致细胞凋亡。抑癌基因TXNIP的表达增加，而与淋巴瘤患者预后不良有关的GPX1和GPX4表达下降。与SUDHL2和SUDHL4细胞在处理后表现出降低的GSH / GSSG比值不同，在KMH2细胞中，该比值保持不变，而谷胱甘肽还原酶和谷胱甘肽的表达增加。由于KMH2细胞对[Au（d2pype）2] Cl处理的敏感性较低，因此TrxR抑制后，GSH系统可能在保护细胞免于凋亡中发挥作用。总体而言，我们的研究表明抑制TrxR代表淋巴瘤的有效治疗方法。而谷胱甘肽还原酶和谷胱甘肽表达增加。由于KMH2细胞对[Au（d2pype）2] Cl处理的敏感性较低，因此TrxR抑制后，GSH系统可能在保护细胞免于凋亡中发挥作用。总的来说，我们的研究表明抑制TrxR代表淋巴瘤的有效治疗方法。而谷胱甘肽还原酶和谷胱甘肽表达增加。由于KMH2细胞对[Au（d2pype）2] Cl处理的敏感性较低，因此TrxR抑制后，GSH系统可能在保护细胞免于凋亡中发挥作用。总体而言，我们的研究表明抑制TrxR代表淋巴瘤的有效治疗方法。