The thioredoxin system mediates redox-induced cell death in human colon cancer cells: implications for the mechanism of action of anticancer agents.
The thioredoxin system mediates redox-induced cell death in human colon cancer cells: implications for the mechanism of action of anticancer agents.
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DOI：
10.1158/0008-5472.can-08-2010
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Rigas B
中科院分区：
文献类型：
--
作者：
Sun Y;Rigas B
抗癌剂至少部分地通过诱导活性氧和氮物种(RON)起作用。研究了三氧化二砷、磷酸阿司匹林、磷酸舒林酸和一氧化氮供体阿司匹林(NO-ASA)四种抗癌化合物对SW480和HT-29结肠癌细胞的氧化还原作用。用普通RONS分子探针检测，所有化合物均能抑制两种细胞系(IC50s 10-90μM)的生长并诱导RON。NO-ASA可诱导至少4种RONS(NO、H_2O_2、超氧阴离子和过氧核糖核酸)诱导的细胞凋亡和坏死性细胞死亡是由RONS介导的(细胞死亡与RONS水平平行，可被N-乙酰半胱氨酸消除，但不能被表现出促氧化活性和促进细胞死亡的二苯基碘离子所抑制)。核转录因子κB和MAPKs受RONS调控。硫氧还蛋白-1(Trx-1)是一种参与氧化还原调节的氧化还原酶，在RONS的作用下被严重氧化，并介导了抗癌药物的生长抑制作用；通过siRNA下调TRX-1的表达可以阻止它们诱导的细胞死亡。这些化合物还抑制硫氧还蛋白还原酶的活性，而硫氧还蛋白还原酶抑制剂金硫代马来酸酯与NO-AsA在诱导细胞死亡方面具有协同作用。我们的发现表明，TRX系统在很大程度上介导了抗癌药物对氧化还原诱导的细胞死亡的反应。这种作用机制可能会被更多的抗癌药物所共享，并值得进一步评估，作为癌症药物控制的候选机制。
Anticancer agents act, at least in part, by inducing reactive oxygen and nitrogen species (RONS). We examined the redox effect on SW480 and HT-29 colon cancer cells of four anticancer compounds, arsenic trioxide, phospho-aspirin, phospho-sulindac and nitric oxide-donating aspirin (NO-ASA). All compounds inhibited the growth of both cell lines (IC50s 10–90 μM) and induced RONS detected by a general RONS molecular probe. NO-ASA, which induced at least four individual RONS (NO, H2O2, superoxide anion and peroxynitirte) induced apoptotic and necrotic cell death that was RONS-mediated (cell death paralleled RONS levels and was abrogated by N-acetyl cysteine, but not by diphenylene iodonium, which displayed prooxidant activity and enhanced cell death). NF-κB and MAPKs were modulated by RONS. Thioredoxin-1 (Trx-1), an oxidoreductase involved in redox-regulation, was heavily oxidized in response to RONS and mediated the growth inhibitory effect of the anticancer agents; knocking-down trx-1 expression by siRNA abrogated cell death induced by them. These compounds also inhibited the activity of thioredoxin reductase that reduces oxidized Trx-1, whereas the thioredoxin reductase inhibitor aurothiomalate synergized with NO-ASA in the induction of cell death. Our findings indicate that the Trx system mediates to a large extent redox-induced cell death in response to anticancer agents. This mechanism of action may be shared by more anticancer agents and deserves further assessment as a candidate mechanism for the pharmacological control of cancer.