Tonissen Kathryn F, Di Trapani Giovanna
School of Biomolecular and Physical Sciences, Griffith University, Nathan, Qld, Australia.
Mol Nutr Food Res. 2009 Jan;53(1):87-103. doi: 10.1002/mnfr.200700492.
The thioredoxin (Trx) system is a major antioxidant system integral to maintaining the intracellular redox state. It contains Trx, a redox active protein, which regulates the activity of various enzymes including those that function to counteract oxidative stress within the cell. Trx can also scavenge reactive oxygen species (ROS) and directly inhibits proapoptotic proteins such as apoptosis signal-regulating kinase 1 (ASK1). The oxidized form of Trx is reduced by thioredoxin reductase (TrxR). The cytoplasm and mitochondria contain equivalent Trx systems and inhibition of either system can lead to activation of apoptotic signaling pathways. There are a number of inhibitors with chemotherapy applications that target either Trx or TrxR to induce apoptosis in cancer cells. Suberoylanilide hydroxamic acid (SAHA) is effective against many cancer cells and functions by up-regulating an endogenous inhibitor of Trx. Other compounds target the selenocysteine-containing active site of TrxR. These include gold compounds, platinum compounds, arsenic trioxide, motexafin gadolinium, nitrous compounds, and various flavonoids. Inhibition of TrxR leads to an accumulation of oxidized Trx resulting in cellular conditions that promote apoptosis. In addition, some compounds also convert TrxR to a ROS generating enzyme. The role of Trx system inhibitors in cancer therapy is discussed in this review.
硫氧还蛋白（Trx）系统是维持细胞内氧化还原状态不可或缺的主要抗氧化系统。它包含Trx，一种具有氧化还原活性的蛋白质，可调节多种酶的活性，包括那些在细胞内对抗氧化应激的酶。Trx还可以清除活性氧（ROS），并直接抑制促凋亡蛋白，如凋亡信号调节激酶1（ASK1）。Trx的氧化形式由硫氧还蛋白还原酶（TrxR）还原。细胞质和线粒体中含有等效的Trx系统，抑制任何一个系统都可导致凋亡信号通路的激活。有许多用于化疗的抑制剂靶向Trx或TrxR以诱导癌细胞凋亡。辛二酰苯胺异羟肟酸（SAHA）对许多癌细胞有效，其作用机制是上调Trx的内源性抑制剂。其他化合物靶向TrxR含硒代半胱氨酸的活性位点。这些化合物包括金化合物、铂化合物、三氧化二砷、莫特沙芬钆、亚硝基化合物和各种黄酮类化合物。抑制TrxR会导致氧化型Trx的积累，从而产生促进细胞凋亡的细胞内环境。此外，一些化合物还可将TrxR转化为产生活性氧的酶。本文综述了Trx系统抑制剂在癌症治疗中的作用。
