Thioredoxin Reductase as a Potential Molecular Target for Anticancer Agents That Induce Oxidative Stress

Smart, Dee Dee; Ortiz, Karen L.; Mattson, David; Bradbury, C. Matthew; Bisht, Kheem S.; Sieck, Leah K.; Brechbiel, Martin W.; Gius, David

doi:10.1158/0008-5472.can-03-3990

Cited by 112 publications

(92 citation statements)

References 44 publications

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“…It has recently been highlighted as an attractive target for anticancer agent activity (55). In the present study, combined treatment with MGd and zinc inhibited cell proliferation (Figs.…”

Section: Discussionsupporting

confidence: 61%

Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

et al. 2005

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To gain a better understanding of the mechanism of action of the metal cation-containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer. (Cancer Res 2005; 65(9): 3837-45)

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“…It has recently been highlighted as an attractive target for anticancer agent activity (55). In the present study, combined treatment with MGd and zinc inhibited cell proliferation (Figs.…”

Section: Discussionsupporting

confidence: 61%

Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

et al. 2005

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“…Selenium is known as a trace element with potent cancer prevention function (19,20). On the other hand, since overexpression of TR1 is consistently observed in many tumors and several antitumor drugs are known inhibitors of TR1 (29 -31), this selenoenzyme was proposed as a target for tumor therapy (7,9,10,15,32). In addition, selenium deficiency has been reported to decrease tumor incidence in some cancer models in animals (33).…”

Section: Discussionmentioning

confidence: 99%

Thioredoxin Reductase 1 Deficiency Reverses Tumor Phenotype and Tumorigenicity of Lung Carcinoma Cells

Yoo

Carlson

et al. 2006

Journal of Biological Chemistry

244

191

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Dietary selenium has potent cancer prevention activity. Both low molecular weight selenocompounds and selenoproteins are implicated in this effect. Thioredoxin reductase 1 (TR1) is one of the major antioxidant and redox regulators in mammals that supports p53 function and other tumor suppressor activities. However, this selenium-containing oxidoreductase is also overexpressed in many malignant cells and has been proposed as a target for cancer therapy. To further assess the role of TR1 in the malignancy process, we used RNA interference technology to decrease its expression in mouse lung carcinoma (LLC1) cells. Stable transfection of LLC1 cells with a small interfering RNA construct that specifically targets TR1 removal manifested a reversal in the morphology and anchorageindependent growth properties of these cancer cells that made them similar to those of normal cells. The expression of at least two cancer-related protein mRNAs, Hgf and Opn1, were reduced dramatically in the TR1 knockdown cells. Mice injected with the TR1 knockdown showed a dramatic reduction in tumor progression and metastasis compared with those mice injected with the corresponding control vector. In addition, tumors that arose from injected TR1 knockdown cells lost the targeting construct, suggesting that TR1 is essential for tumor growth in mice. These observations provide direct evidence that the reduction of TR1 levels in malignant cells is antitumorigenic and suggest that the enzyme is a prime target for cancer therapy.There are 25 selenoproteins in humans and 24 in rodents (1), and of those with known functions, most serve as antioxidants (reviewed in Refs. 2 and 3). One of these selenoproteins, thioredoxin reductase 1 (TR1), 2 is one of the major antioxidant and redox regulators in mammalian cells. TR1 is an essential protein (4) that is expressed in all cell types and organs (2, 3), and the Sec moiety is essential for its activity (5, 6). Interestingly, it is overexpressed in many malignant cells (e.g. see Refs. 7-10). A variety of potent TR1 inhibitors have been shown to alter the cancer-related properties of tumors and numerous malignant cells (see Refs. 7-13 and references therein). For example, recently, a potent antitumor drug, 1,2-[bis (2-benzysoselenazolone-3(2H)-ketone)]ethane, was found to reverse the phenotype of five human carcinoma cell lines (13). Furthermore, reduction of TR1 activity in human hepatocellular carcinoma cells by transfection with TR1 antisense RNA inhibited cell growth (14). TR1 has therefore been implicated as a potential target for cancer therapy (e.g. see Refs. 7, 9, 10, and 15).On the other hand, TR1 is a selenoprotein that activates tumor suppressor p53 (16) and is specifically targeted by carcinogenic electrophiles (17,18). Dietary selenium also has potent cancer prevention activity (see Refs. 19 and 20 and references therein). These latter studies have implicated TR1 in tumor suppression, and thus, the overall role of TR1 in tumor progression remains unclear. To further assess the role of TR1 in tu...

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“…by the creation of chemotherapy resistance in cancer cells induced by overproduction of Trx, which has been demonstrated for example in patients receiving cisplatin (Yokomizo et al 1995;Sasada et al 1996;Karlenius and Tonissen 2010). In early stage cancer patients, who are commonly treated by radiotherapy, Trx system was identified as a potential modulator of radiosensitivity (Smart et al 2004;Mehta et al 2009). …”

Section: Expression Of Thioredoxin System Proteins During Oxidative Smentioning

confidence: 99%

Thioredoxin system – a novel therapeutic target

Koháryová¹,

Kollárová²

2015

gpb

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Abstract. Nowadays there are numerous pathogens that have created a resistance to commonly used antibiotics and drugs. Therefore research is focused on finding new therapeutic targets and on determination of their 3D structures that could help in designing new effective substances and inhibitors. Thioredoxin system not only plays a crucial role as thiol/disulfide redox controller, it is also essential for certain organisms as the only system ensuring the redox homeostasis. It is the redox-regulating function, which makes thioredoxin and thioredoxin reductase attractive for scientific research, especially in many studies of diseases caused by redox instability. Thanks to these facts, the proteins of thioredoxin system are suitable candidates for new therapeutic purposes. In this review we summarized the basic features of the thioredoxin system, we justified why the proteins of thioredoxin system are appropriate therapeutical targets and we provided overview of the possibilities of their inhibition by several types of inhibitors.

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Thioredoxin Reductase as a Potential Molecular Target for Anticancer Agents That Induce Oxidative Stress

Cited by 112 publications

References 44 publications

Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

Thioredoxin Reductase 1 Deficiency Reverses Tumor Phenotype and Tumorigenicity of Lung Carcinoma Cells

Thioredoxin system – a novel therapeutic target

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