High levels of thioredoxin reductase 1 modulate drug-specific cytotoxic efficacy

Eriksson, Sofi; Prast‐Nielsen, Stefanie; Flaberg, Emilie; Szekeres, L.; Arnér, Elias S.J.

doi:10.1016/j.freeradbiomed.2009.09.016

Cited by 118 publications

(92 citation statements)

References 67 publications

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“…Since Trr1 is recognized as an anticancer drug target, recent study has focused on the importance of Trr1 in drugspecific cytotoxic efficacy in response to various anticancer agents in the human lung carcinoma A549 cell line expressing a very high basal level of Trr1 (29). In accordance with these observations, our results showed for the first time that cellular sensitivity to MMC was dramatically increased in the Trr1 shRNA knockdown cells relative to the wild-type RKO cells (Fig.…”

Section: Discussionsupporting

confidence: 87%

Enhancement of the efficacy of mitomycin C-mediated apoptosis in human colon cancer cells with RNAi-based thioredoxin reductase 1 deficiency

Koedrith

Seo

2011

Experimental and Therapeutic Medicine

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Abstract. Thioredoxin reductase 1 (Trr1) is an antioxidant and redox regulator that functions in governing the cellular redox state and survival against oxidative insults in mammals. However, this selenoprotein is also overexpressed in various forms of malignant cancers, leading to the hypothesis that Trr1 may be a potential target for cancer therapy. A quinone anticancer drug, mitomycin C (MMC), has been clinically used in the treatment of several types of tumors, including those of the colon. MMC exerts its activity via ROS induction and further results in DNA cross-linkage. To evaluate the significant role of Trr1 in MMC resistance in human colon cancer (RKO) cells, specific reduction in the expression of Trr1 was achieved using short-hairpin RNA (shRNA)-based interference. Our results showed that stable Trr1 shRNA knockdown manifested higher cellular susceptibility to MMC in comparison to that in wild-type cells. In addition, increased intracellular ROS accumulation appeared in the Trr1 shRNA knockdown cells compared to the RKO wild-type cells, in proportion to a relatively higher fraction of the DNA damage reporter protein phosphorylated histone 'γ-H2AX'. Notably, a neutral comet assay demonstrated that DNA double-strand breaks were highly induced in the Trr1-deficient cancer cells in the presence of MMC, presumably stimulating cancer cell death. Our results also revealed that MMC-induced apoptosis was associated with enhancement of oxidative damage to DNA. These results suggest that the specific knockdown of Trr1 expression via shRNA vector interference technology may be a potent molecular strategy by which to enhance the effectiveness of MMC-mediated killing in human colon cancer cells, through acceleration of double-strand DNA damage-oxidative stress as a trigger for apoptosis. This implies that Trr1 may be a prime target for enhancing the effectiveness of MMC chemotherapy in combination with specific RNA interference.

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Section: Discussionsupporting

confidence: 87%

Enhancement of the efficacy of mitomycin C-mediated apoptosis in human colon cancer cells with RNAi-based thioredoxin reductase 1 deficiency

Koedrith

Seo

2011

Experimental and Therapeutic Medicine

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“…Actually, TXNRD levels as well as TXNRD activity were increased in drugresistant cells, 35,36 and high TXNRD levels actually interfered with drug-specific cytotoxic efficacy in vitro. 37 In the present study, some esophageal cancer cases also showed TNXRD expression in tumor surrounding stromal cells, which may be related to inflammation. Indeed, similar observations were made for macrophages and reactive fibroblasts in breast cancer.…”

Section: Discussionsupporting

confidence: 56%

Response of esophageal cancer cells to epigenetic inhibitors is mediated via altered thioredoxin activity

Ahrens

Timme

Ostendorp

et al. 2016

Laboratory Investigation

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We previously showed that histone deacetylase inhibitor (HDACi) and 5-azacytidine (AZA) treatment selectively induced cell death of esophageal cancer cells. The mechanisms of cancer selectivity, however, remained unclear. Here we examined whether the cancer selectivity of HDACi/AZA treatment is mediated by the thioredoxin (Trx) system and reactive oxygen species (ROS) in esophageal cancer cells. For this, we first analyzed human tissue specimens of 37 esophageal cancer patients by immunohistochemistry for Trx, Trx-interacting protein (TXNIP) and Trx reductase (TXNRD). This revealed a loss or at least reduction of nuclear Trx in esophageal cancer cells, compared with normal epithelial cells (Po0.001). Although no differences were observed for TXNIP, TXNRD was more frequently expressed in cancer cells (Po0.001). In the two main histotypes of esophageal squamous cell carcinomas (ESCCs, n = 19) and esophageal adenomcarcinomas (EAC, n = 16), similar Trx, TXNIP and TXNRD expression patterns were observed. Also in vitro, nuclear Trx was only detectable in non-neoplastic Het-1A cells, but not in OE21/ESCC or OE33/EAC cell lines. Moreover, the two cancer cell lines showed an increased Trx activity, being significant for OE21 (P = 0.0237). After treatment with HDACi and/or AZA, ROS were exclusively increased in both cancer cell lines (P = 0.048-0.017), with parallel decrease of Trx activity. This was variably accompanied by increased TXNIP levels upon AZA, MS-275 or MS-275/AZA treatment for 6 or 24 h in OE21, but not in Het-1A or OE33 cells. In summary, this study evaluated Trx and its associated proteins TXNIP and TXNRD for the first time in esophageal cancers. The analyses revealed an altered subcellular localization of Trx and strong upregulation of TXNRD in esophageal cancer cells. Moreover, HDACi and AZA disrupted Trx function and induced accumulation of ROS with subsequent apoptosis in esophageal cancer cells exclusively. Trx function is hence an important cellular mediator conferring non-neoplastic cell resistance for HDACi and/or AZA.

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“…However, direct oxidation of Trx in cells by the metal complexes of the thiosemicarbazones cannot be excluded. This is suggested considering that previous studies have shown that even with a 90% knockdown of thioredoxin reductase, there was little effect on downstream thioredoxin and thioredoxin-dependent functions because of the residual capacity of the enzyme (Eriksson et al, 2009). It is known that mammalian TrxR has broad specificity (Arnér, 2009), and many electrophilic compounds can affect TrxR activity (Chew et al, 2008).…”

Section: Discussionmentioning

confidence: 98%

The Potent and Novel Thiosemicarbazone Chelators Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-Benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone Affect Crucial Thiol Systems Required for Ribonucleotide Reductase Activity

Yu¹,

Rahmanto²,

Hawkins³

et al. 2011

Mol Pharmacol

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Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone possesses potent and selective antitumor activity. Its cytotoxicity has been attributed to iron chelation leading to inhibition of the ironcontaining enzyme ribonucleotide reductase (RR). Thiosemicarbazone iron complexes have been shown to be redox-active, although their effect on cellular antioxidant systems is unclear. Using a variety of antioxidants, we found that only N-acetylcysteine significantly inhibited thiosemicarbazone-induced antiproliferative activity. Thus, we examined the effects of thiosemicarbazones on major thiol-containing systems considering their key involvement in providing reducing equivalents for RR. Thiosemicarbazones significantly (p Ͻ 0.001) elevated oxidized trimeric thioredoxin levels to 213 Ϯ 5% (n ϭ 3) of the control. This was most likely due to a significant (p Ͻ 0.01) decrease in thioredoxin reductase activity to 65 Ϯ 6% (n ϭ 4) of the control. We were surprised to find that the non-redox-active chelator desferrioxamine increased thioredoxin oxidation to a lower extent (152 Ϯ 9%; n ϭ 3) and inhibited thioredoxin reductase activity (62 Ϯ 5%; n ϭ 4), but at a 10-fold higher concentration than thiosemicarbazones. In contrast, only the thiosemicarbazones significantly (p Ͻ 0.05) reduced the glutathione/oxidized-glutathione ratio and the activity of glutaredoxin that requires glutathione as a reductant. All chelators significantly decreased RR activity, whereas the NADPH/ NADP total ratio was not reduced. This was important to consider because NADPH is required for thiol reduction. Thus, thiosemicarbazones could have an additional mechanism of RR inhibition via their effects on major thiol-containing systems.

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High levels of thioredoxin reductase 1 modulate drug-specific cytotoxic efficacy

Cited by 118 publications

References 67 publications

Enhancement of the efficacy of mitomycin C-mediated apoptosis in human colon cancer cells with RNAi-based thioredoxin reductase 1 deficiency

Enhancement of the efficacy of mitomycin C-mediated apoptosis in human colon cancer cells with RNAi-based thioredoxin reductase 1 deficiency

Response of esophageal cancer cells to epigenetic inhibitors is mediated via altered thioredoxin activity

The Potent and Novel Thiosemicarbazone Chelators Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-Benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone Affect Crucial Thiol Systems Required for Ribonucleotide Reductase Activity

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