Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of and did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth and . Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.

中文翻译：

---

类风湿关节炎药物金诺芬通过刺激 TXNRD 介导的 ROS 生成和抑制能量代谢发挥有效的抗淋巴瘤作用


由于疾病进展或复发的淋巴瘤患者的生存率仍然很低，因此迫切需要新的治疗方法和有效的药物。在这里，我们发现金诺芬（AF）是一种抗风湿药物，被认为以抑制硫氧还蛋白还原酶（TXNRD）作为其作用机制，对多种癌症类型表现出有效的活性，特别是对 B 细胞淋巴瘤有效。令人惊讶的是，敲低 和 并没有引起显着的细胞毒性，这表明 TXNRD 酶的废除不足以导致癌细胞死亡。进一步的机理研究表明，AF 与 TXNRD 的相互作用可以通过破坏其电子传输，将这种抗氧化酶转化为 ROS 生成分子，导致电子泄漏，与分子氧相互作用形成超氧化物。 AF 还通过抑制线粒体复合物 II 和糖酵解酶 GAPDH 来抑制能量代谢，从而导致 ATP 显着消耗并抑制癌症生长。重要的是，我们发现 AF 介导的 ROS 应激可以诱导 PD-L1 表达，揭示了 AF 在引起免疫抑制方面的不良影响。我们进一步表明，AF 与抗 PD-1 抗体的组合可以增强同基因免疫活性小鼠 B 细胞淋巴瘤模型的抗癌活性。我们的研究表明，AF 可能是治疗淋巴瘤的潜在药物，其与免疫检查点抑制剂的组合将是增加治疗活性的合理策略。