Inhibition of Both Thioredoxin Reductase and Glutathione Reductase may Contribute to the Anticancer Mechanism of TH-302
Inhibition of Both Thioredoxin Reductase and Glutathione Reductase may Contribute to the Anticancer Mechanism of TH-302
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DOI：
10.1007/s12011-009-8544-1
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发表时间：
2010-09-01
影响因子：
3.9
通讯作者：
Duan, Jian-Xin
中科院分区：
文献类型：
--
作者：
Li, Shengrong;Zhang, Jinsong;Duan, Jian-Xin
含硒硫氧还蛋白还原酶（TrxR）是肿瘤治疗的重要靶点。已知许多有用的抗癌剂，包括双烷基化剂、顺铂和三氧化二砷，与硫氧还蛋白还原酶的羧基末端区域中的硒代半胱氨酸二肽相互作用，并破坏其还原硫氧还蛋白的能力。一些研究人员推测，TrxR的失活可能会增加这些抗癌药物的细胞毒性潜力。TH-302是一种新开发的抗肿瘤药物，代表了一类潜在的新型肿瘤选择性缺氧激活前药（HAPs）。TH-302是一种无活性的前药，通过2-硝基咪唑作为氧传感器与溴异磷酰胺（Br-IPM）的共价结合而产生。在严重缺氧和近缺氧的存在下，两个咪唑传感器部分进行还原和Br-IPM原位释放。溴-IPM是氯-IPM的更潜在类似物，氯-IPM是通过异环磷酰胺（IFO）活化而衍生的活性烷基化部分。我们先前证明IFO可以抑制肿瘤TrxR活性，并且已知氯-IPM与硫氧还蛋白还原酶中的硒代半胱氨酸二肽共价结合。本研究评估了TH-302在荷肝癌22（H22）小鼠肿瘤中活化并抑制肿瘤TrxR的能力。在荷肝癌22（H22）实体瘤的小鼠中，腹膜内（i. p.）以200 mg/kg的剂量注射TH-302给药两次（小鼠耐受良好的方案），显著抑制肿瘤生长。同样在该小鼠模型中，300 mg/kg剂量的腹膜内TH-302（其将是小鼠耐受的最大单次腹膜内施用剂量，并且仅诱导2%体重减轻）显著抑制TrxR和谷胱甘肽还原酶（GR）活性46%。与对照组相比，注射后3 h，分别为60%（P <0.001）和60%（P < 0.001）。由于TrxR是硫氧还蛋白系统中的关键参与者，而GR是谷胱甘肽系统中还原氧化型谷胱甘肽的主要还原酶，因此本研究结果暗示TH-302的抗癌作用与TrxR和GR的调节同时相关。这些发现表明TH-302在该模型系统中的抗癌活性可能与DNA烷基化以及TrxR和GR的调节有关。此外，他们提出，通过抑制这两种关键的还原酶，用较少的谷胱甘肽来拦截参与DNA烷基化的活性中间体，化疗的抗肿瘤作用将增强。
Selenium-containing thioredoxin reductase (TrxR) is an important target of cancer therapy. Many useful anticancer agents including bis-alkylating agents, cisplatin, and arsenic trioxide are known to interact with the selenocysteine dipeptide in the carboxy terminal region of thioredoxin reductase and inactivate its ability to reduce thioredoxin. Some investigators have postulated that the inactivation of TrxR may add to the cytotoxic potential of these anticancer agents. TH-302 is a newly developed antineoplastic drug which represents a potential new class of tumor selective hypoxia-activated prodrugs (HAPs). TH-302 is an inactive prodrug created by the covalent conjugation of 2-nitroimidazole as an oxygen sensor to bromo-isophosphoramide (Br-IPM). In the presence of severe hypoxia and near anoxia, the two imidazole sensor moiety undergoes reduction and the Br-IPM is released in situ. Bromo-IPM is a more potential analog of Chloro-IPM, the active alkylating moiety that is derived by activation of ifosfamide (IFO). We previously demonstrated that IFO could inhibit tumor TrxR activity and chloro-IPM is known to bind covalently to the seleno-cysteine dipeptide in thioredoxin reductase. The present study assessed the ability of TH-302 to activate in the tumors of mice-bearing hepatoma 22 (H22) and inactivate the tumor TrxR. In mice-bearing hepatoma 22 (H22) solid tumors, intraperitoneal (i.p.) injection with TH-302 at the dose of 200 mg/kg administered twice, a regimen which was well tolerated by the mice, significantly inhibited tumor growth. Also in this mice model, i.p. TH-302 at the dose of 300 mg/kg, which would be the maximum single i.p. administration dose tolerated by mice, and which induced only 2% body weight loss, significantly inhibited both TrxR and glutathione reductase (GR) activities by 46% (P < 0.001) and 60% (P < 0.001) as compared with the controls, respectively, at 3 h after the injection. Since TrxR is a key player in thioredoxin system and GR is the major reductase for the reduction of oxidized glutathione in glutathione system, the present results imply the anticancer effect of TH-302 is associated concurrently with modulation of TrxR and GR. These findings suggest that the anticancer activity of TH-302 in this model system may associate with both DNA alkylation and the modulation of TrxR and GR. In addition, they suggest that, by inhibition of these two critical reductases, with less glutathione available to intercept the reactive intermediates involved in DNA alkylation, the antitumor effects of the chemotherapy would be enhanced.