Up-regulation of thioredoxin and thioredoxin reductase in human malignant pleural mesothelioma

Kahlos, Katriina; Soini, Ylermi; Säily, Marjaana; Koistinen, Pirjo; Kakko, Sakari; Pääkkö, Paavo; Holmgren, Arne; Kinnula, Vuokko L.

doi:10.1002/1097-0215(20010520)95:3<198::aid-ijc1034>3.0.co;2-f

Cited by 113 publications

(77 citation statements)

References 52 publications

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“…TRx is a strong redox regulator and involves in many normal cellular functions. However, it is also known that TRx levels are high in many cancerous cells (Gallegos et al, 2000,Kahlos et al, 2001) while lower TRx levels are associated with some degenerative diseases such as Alzheimer (Lovell et al, 2000). Therefore, proper regulation of TRx bioavailability is of vital importance to the cells and tissues.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2)

Liyanage

Fernando

Lou

2007

Experimental Eye Research

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Thioredoxin (TRx) is known to control redox homeostasis in cells. In recent years, a specific TRx binding protein called thioredoxin binding protein-2 (TBP-2) was found in other cell types and it appeared to negatively regulate TRx bioavailability and thereby control TRx biological function. In view of the sensitivity of lens transparency to redox status, proper regulation of TRx bioavailability is of the utmost importance. This study was conducted to examine the presence and function of TBP-2 in human lens epithelial cells (HLE B3). We cloned human lens TBP-2 from a human cDNA library (GenBank accession number AY 594328) and showed that it is fully homologous to the human brain TBP-2 gene. The recombinant TBP-2 protein was partially purified and mass spectrometric analysis confirmed its sequence homology to that of brain TBP-2. Immunoprecipitates obtained from HLE B3 cells using anti-TRx and anti-TBP-2 antibodies showed the presence of TRx and TBP-2 in immunoprecipitates indicating the formation of a TRx-TBP-2 complex in vivo. Furthermore, under H 2 O 2 -stress conditions, TRx gene expression was transiently up-regulated while TBP-2 gene expression was inversely down-regulated as seen in both HLE B3 cells and in the epithelial cell layers from cultured pig lenses. Cells with overexpressed TBP-2 showed lower TRx activity, grew slower and were more susceptible to oxidative stress-induced apoptosis. This is the first report of the presence of a TRx-specific binding protein in the lens. Our data suggest that TBP-2 is likely a negative regulator for the bioavailability, and therefore, the overall function of TRx in the lens.

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Section: Discussionmentioning

confidence: 99%

Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2)

Liyanage

Fernando

Lou

2007

Experimental Eye Research

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“…29 Over-expression of thioredoxin reductase 1 has been reported in several tumour types and the enzyme is an important therapeutic target in anti-cancer drug development. [30][31][32] In order to investigate the mode of action of our novel complexes, the inhibition of Trx-R activity by complexes 1, 15, 16 and 18 was investigated. Previously, a range of iridium picolinamide complexes were found to inhibit Trx-R, with IC50 values in the nanomolar range.…”

Section: Inhibition Of Thioredoxin Reductase Activitymentioning

confidence: 99%

Hypoxia-Sensitive Metal β-Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis

et al. 2015

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A series of ruthenium and iridium complexes have been synthesised and characterised with 20 novel crystal structures discussed. The library of -ketoiminato complexes has been shown to be active against MCF-7 (human breast carcinoma), HT-29 (human colon carcinoma), A2780 (human ovarian carcinoma) and A2780cis (cisplatin resistant human ovarian carcinoma) cell lines, with selected complexes being more than three times as active as cisplatin against the A2780cis cell line. Complexes have also been shown to be highly active under hypoxic conditions, with the activities of some complexes increasing with a decrease in O2 concentration. The enzyme thioredoxin reductase is over-expressed in cancer cells and complexes reported herein have the advantage of inhibiting this enzyme, with IC50 values measured in the nanomolar range. The anti-cancer activity of these complexes was further investigated to determine whether activity is due to effects on cellular growth or cell survival. The complexes were found to induce significant cancer cell death by apoptosis with levels induced correlating closely with activity in chemosensitivity studies. As a possible cause of cell death, the ability of the complexes to induce damage to cellular DNA was also assessed. The complexes failed to induce double strand DNA break or DNA crosslinking but induced significant levels of single DNA strand breaks indicating a different mechanism of action to cisplatin.

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“…Therefore, inhibition of thioredoxin can have antiproliferative and proapoptotic effects (Pallis et al, 2003). Thioredoxin is upregulated in a wide variety of tumours such as mesothelioma (Kahlos et al, 2001), leukaemia (Shao et al, 2001), lung (Kakolyris et al, 2001), hepatocellular (Miyazaki et al, 1998) and renal cancer (Lichtenfels et al, 2003). Colorectal cancer tissues have also been shown to overexpress thioredoxin and hence thioredoxin could be an important therapeutic target for colon cancer (Raffel et al, 2003).…”

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confidence: 99%

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

et al. 2005

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AW464 (NSC 706704) is a novel benzothiazole substituted quinol compound active against colon, renal and certain breast cancer cell lines. NCI COMPARE analysis indicates possible interaction with thioredoxin/thioredoxin reductase, which is upregulated under hypoxia. Through activity on HIF1a, VEGF levels are regulated and angiogenesis controlled. A thioredoxin inhibitor could therefore exhibit enhanced hypoxic toxicity and indirect antiangiogenic effects. In vitro experiments were performed on colorectal and breast cancer cell lines under both normoxic and hypoxic conditions and results compared against those obtained with normal cell lines, fibroblasts and keratinocytes. Antiangiogenic effects were studied using both large and microvessel cells. Indirect antiangiogenic effects (production of angiogenic growth factors) were studied via ELISA. We show that AW464 exerts antiproliferative effects on tumour cell lines as well as endothelial cells with an IC 50 of B0.5 mM. Fibroblasts are however resistant. Proliferating, rather than quiescent, endothelial cells are sensitive to the drug indicating potential antiangiogenic rather than antivascular action. Endothelial differentiation is also inhibited in vitro. Hypoxia (1% O 2 for 48 h) sensitises colorectal cells to lower drug concentrations, and in HT29s greater inhibition of VEGF is observed under such conditions. In contrast, bFGF levels are unaffected, suggesting possible involvement of HIF1a. Thus, AW464 is a promising chemotherapeutic drug that may have enhanced potency under hypoxic conditions and also additional antiangiogenic activity.

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Up-regulation of thioredoxin and thioredoxin reductase in human malignant pleural mesothelioma

Cited by 113 publications

References 52 publications

Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2)

Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2)

Hypoxia-Sensitive Metal β-Ketoiminato Complexes Showing Induced Single-Strand DNA Breaks and Cancer Cell Death by Apoptosis

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

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