Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Department of Selenoprotein Research, National Institute of Oncology, Budapest, Hungary.
Handb Exp Pharmacol. 2021;264:289-309. doi: 10.1007/164_2020_393.
The mammalian thioredoxin system is driven by NADPH through the activities of isoforms of the selenoprotein thioredoxin reductase (TXNRD, TrxR), which in turn help to keep thioredoxins (TXN, Trx) and further downstream targets reduced. Due to a wide range of functions in antioxidant defense, cell proliferation, and redox signaling, strong cellular aberrations are seen upon the targeting of TrxR enzymes by inhibitors. However, such inhibition can nonetheless have rather unexpected consequences. Accumulating data suggest that inhibition of TrxR in normal cells typically yields a paradoxical effect of increased antioxidant defense, with metabolic pathway reprogramming, increased cellular proliferation, and altered cellular differentiation patterns. Conversely, inhibition of TrxR in cancer cells can yield excessive levels of reactive oxygen species (ROS) resulting in cell death and thus anticancer efficacy. The observed increases in antioxidant capacity upon inhibition of TrxR in normal cells are in part dependent upon activation of the Nrf2 transcription factor, while exaggerated ROS levels in cancer cells can be explained by a non-oncogene addiction of cancer cells to TrxR1 due to their increased endogenous production of ROS. These separate consequences of TrxR inhibition can be utilized therapeutically. Importantly, however, a thorough knowledge of the molecular mechanisms underlying effects triggered by TrxR inhibition is crucial for the understanding of therapy outcomes after use of such inhibitors. The mammalian thioredoxin system is driven by thioredoxin reductases (TXNRD, TrxR), which keeps thioredoxins (TXN, Trx) and further downstream targets reduced. In normal cells, inhibition of TrxR yields a paradoxical effect of increased antioxidant defense upon activation of the Nrf2 transcription factor. In cancer cells, however, inhibition of TrxR yields excessive reactive oxygen species (ROS) levels resulting in cell death and thus anticancer efficacy, which can be explained by a non-oncogene addiction of cancer cells to TrxR1 due to their increased endogenous production of ROS. These separate consequences of TrxR inhibition can be utilized therapeutically.
哺乳动物硫氧还蛋白系统由 NADPH 通过硒蛋白硫氧还蛋白还原酶（TXNRD，TrxR）同工型的活性驱动，其反过来有助于保持硫氧还蛋白（TXN，Trx）和下游进一步的靶标还原。由于在抗氧化防御、细胞增殖和氧化还原信号传导方面具有广泛的功能，因此 TrxR 酶被抑制剂靶向时会出现强烈的细胞异常。然而，这种抑制作用仍然可能产生意想不到的后果。越来越多的数据表明，正常细胞中 TrxR 的抑制通常会产生一种矛盾的效果，即抗氧化防御增加，代谢途径重新编程，细胞增殖增加，细胞分化模式改变。相反，癌细胞中 TrxR 的抑制会产生过量的活性氧物种（ROS），导致细胞死亡，从而产生抗癌疗效。正常细胞中 TrxR 抑制后观察到的抗氧化能力增加部分依赖于 Nrf2 转录因子的激活，而癌细胞中 ROS 水平的夸大可以通过癌细胞对 TrxR1 的非癌基因成瘾来解释，因为它们增加了内源性 ROS 的产生。TrxR 抑制的这些不同后果可用于治疗。然而，重要的是，对 TrxR 抑制触发的作用的分子机制有一个透彻的了解，对于理解使用此类抑制剂后的治疗结果至关重要。哺乳动物硫氧还蛋白系统由硫氧还蛋白还原酶（TXNRD，TrxR）驱动，它使硫氧还蛋白（TXN，Trx）和下游进一步的靶标保持还原状态。在正常细胞中，TrxR 的抑制通过 Nrf2 转录因子的激活产生抗氧化防御增加的矛盾效果。然而，在癌细胞中，TrxR 的抑制会产生过量的活性氧物种（ROS）水平，导致细胞死亡，从而产生抗癌疗效，这可以通过癌细胞对 TrxR1 的非癌基因成瘾来解释，因为它们增加了内源性 ROS 的产生。TrxR 抑制的这些不同后果可用于治疗。
