Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study

Mukherjee, Abhik; Westwell, Andrew D.; Bradshaw, Tracey D.; Stevens, Malcolm F. G.; Carmichael, James; Martin, Stewart G.

doi:10.1038/sj.bjc.6602338

Cited by 52 publications

(48 citation statements)

References 37 publications

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“…Both compounds inhibited VEGF expression at subtoxic concentrations in hypoxic breast and melanoma cell lines and pVHL mutant renal cell lines, with AJM290 being the more potent compound. Studies carried out by Mukherjee et al showed that hypoxia reduced the IC 50 of AW464 by f5-fold in all colorectal cancer cell lines tested (35). However, we saw no changes in IC 50 between hypoxic and normoxic cells and pVHL mutant and stable pVHL-transfected cells following 16 or 48 hours of treatment with AJM290 or AW464.…”

Section: Discussioncontrasting

confidence: 47%

“…However, we saw no changes in IC 50 between hypoxic and normoxic cells and pVHL mutant and stable pVHL-transfected cells following 16 or 48 hours of treatment with AJM290 or AW464. The difference in results could be due to the cell lines used (35).…”

Section: Discussionmentioning

confidence: 90%

“…AW464 is a benzothiazole-substituted quinol compound that has been shown by mass spectrometry to bind to Trx-1 and has been proposed to cross-link irreversibly to cysteine residues 32 and 35 of Trx-1 active site via its two h-carbon atoms; the first link is reversible, whereas the second cross-link is thought to be irreversible (36,41). AW464 can inhibit VEGF expression in hypoxic colorectal cells, and hypoxia has been shown to sensitize colorectal cancer cells to antiproliferative effect of AW464 (35). Further chemical syntheses and structure activity screening uncovered AJM290, an indole-substituted quinol that possess enhanced potency in vitro against human derived colon, renal, and mammary carcinoma cell lines and in vivo antitumor activity against breast, colon, and renal mouse xenografts (36,42).…”

Section: Discussionmentioning

confidence: 99%

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Novel Thioredoxin Inhibitors Paradoxically Increase Hypoxia-Inducible Factor-α Expression but Decrease Functional Transcriptional Activity, DNA Binding, and Degradation

Jones

Pugh

Wigfield

et al. 2006

Clinical Cancer Research

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Purpose: Hypoxia-inducible factor-a (HIF-a) is a transcription factor that regulates the response to hypoxia. HIF-a protein is found at high levels in many cancers, and the redox protein thioredoxin-1 (Trx-1) increases both aerobic and hypoxia-induced HIF-a. Therefore, Trx-1 and HIF-a are attractive molecular targets for novel cancer therapeutics. Experimental Design: We investigated whether two novel anticancer drugs AJM290 and AW464 (quinols), which inhibit Trx-1function, can inhibit the HIF pathway. Results: Treatment of several cancer cell lines with AJM290 or AW464 prevented the hypoxiainduced increase of vascular endothelial growth factor (VEGF) at subtoxic concentrations. AJM290 and AW464 also decreased VEGF in pVHL mutant renal cell carcinoma cells that constitutively overexpress HIF-a protein. They surprisingly up-regulated HIF-a expression in breast cancer cell lines in normoxia and hypoxia as well as in pVHL mutant cells. In the MDA-MB-468 breast cancer cell line, the compounds inhibited RNA and protein expression of the HIF-a target genes, carbonic anhydrase IX, VEGF, and BNIP3, concordantly with HIF-a up-regulation. Both compounds specifically inhibited HIF-a-dependent induction of hypoxia regulatory elementluciferase and HIF-1a hypoxia regulatory element-DNA binding. To analyze the HIF-1a domain inhibited byAJM290, we transfected cells with plasmids expressing a fusion protein of Gal linked to HIF-1a or HIF-1a COOH-terminal transactivation domain (CAD) with a Gal4-responsive luciferase reporter gene. AJM290 inhibited both the full-length HIF-1aand HIF-1aCAD transcriptional activity. Conclusions: AJM290 and AW464 are inhibitors of HIF-1aCAD transcription activity and DNA binding, but they also inhibit degradation of HIF, in contrast to other Trx inhibitors.

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Novel Thioredoxin Inhibitors Paradoxically Increase Hypoxia-Inducible Factor-α Expression but Decrease Functional Transcriptional Activity, DNA Binding, and Degradation

Jones

Pugh

Wigfield

et al. 2006

Clinical Cancer Research

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“…Apparently, this TR1 dichotomy requires the thioredoxin pathway, due to the many targets of this protein. This hypothesis could explain both the potent cancer prevention activity of dietary selenium (19,20) and the potent antitumor activity of drugs that target TR1 (7)(8)(9)(10)(11)(12)(13). Most importantly, this study provides a foundation to explain literature data on the role of TR1 in cancer and establishes this enzyme as a prime target for cancer therapy.…”

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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“…AW464 has anti-proliferative activity on tumor cell lines and endothelial cells in vitro, but not fibroblasts, with IC 50 value of 0.5 µM (Mukherjee et al 2005).…”

Section: Inhibitors Of Trxmentioning

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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Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study

Cited by 52 publications

References 37 publications

Novel Thioredoxin Inhibitors Paradoxically Increase Hypoxia-Inducible Factor-α Expression but Decrease Functional Transcriptional Activity, DNA Binding, and Degradation

Novel Thioredoxin Inhibitors Paradoxically Increase Hypoxia-Inducible Factor-α Expression but Decrease Functional Transcriptional Activity, DNA Binding, and Degradation

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

Thioredoxin system – a novel therapeutic target

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