Abstract：
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 TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se 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 in vitro and in vivo. 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.
摘要：
由于经历疾病进展或复发的淋巴瘤患者的生存率仍然很差，迫切需要新的治疗方法和有效的药物。在这里，我们展示了auranofin(AF)，一种抗类风湿药物，被认为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，对B细胞淋巴瘤特别有效。令人惊讶的是,敲低TXNRD1和TXNRD2并没有引起显著的细胞毒性，表明TXNRD酶本身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递将这种抗氧化酶转化为ROS生成分子。导致与分子氧相互作用形成超氧化物的电子泄漏。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，导致ATP的显着消耗和抑制体外和体内癌症的生长。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作用。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细胞淋巴瘤模型中的抗癌活性。我们的研究表明房颤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乎逻辑的策略。
