Targeting Thioredoxin Reductase: Anticancer Agents and Chemopreventive Compounds

Hh, Zeng; Lh, Wang

doi:10.2174/157340610793358864

Cited by 13 publications

(9 citation statements)

References 77 publications

(125 reference statements)

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“…The thioredoxin system contributes to several proliferative phenomena and is considered to be required for tumor progression [29, 31]. There have been many reports demonstrating that novel and existing compounds, including Carmustine, can act as TrxR inhibitors [28, 37–39]. Investigators have been also been researching the possible biochemical and cellular outcomes of TrxR inhibition, such as the induction of apoptotic pathways upon disruption of TrxR activity [47–49].…”

Section: Discussionmentioning

confidence: 99%

“…TrxR also delivers reducing equivalents to ribonucleotide reductase, which is necessary for the synthesis of deoxyribonucleotides towards the synthesis of DNA [22]. With so many cell proliferative consequences of a robust thioredoxin system, TrxR is increasingly viewed as an attractive target for anticancer agents [26–28]. Both Trx and TrxR are upregulated in malignant cells and their activities are reported to be essential for tumor progression [29].…”

Section: Introductionmentioning

confidence: 99%

“…Any, or all, of these nucleophilic groups could be targets for methyl isocyanate’s carbamoylating activity. The inhibition of TrxR activity has been reported using several reactive electrophiles [37, 38], including many existing antitumor drugs [28, 39]. Reported here is the potent inhibition of TrxR by the methyl isocyanate-bearing anticancer agent Laromustine.…”

Section: Introductionmentioning

confidence: 99%

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Thioredoxin reductase is inhibited by the carbamoylating activity of the anticancer sulfonylhydrazine drug laromustine

et al. 2012

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The thioredoxin system facilitates proliferative processes in cells and is upregulated in many cancers. The activities of both thioredoxin (Trx) and its reductase (TrxR) are mediated by oxidation/reduction reactions among cysteine residues. A common target in preclinical anticancer research, TrxR is reported here to be significantly inhibited by the anticancer agent Laromustine. This agent, which has been in clinical trials for acute myelogenous leukemia and glioblastoma multiforme, is understood to be cytotoxic principally via interstrand DNA crosslinking that originates from a 2-chloroethylating species generated upon activation in situ. The spontaneous decomposition of Laromustine also yields methyl isocyanate, which readily carbamoylates thiols and primary amines. Purified rat liver TrxR was inhibited by Laromustine with a clinically relevant IC50value of 4.65 µM. A derivative of Laromustine that lacks carbamoylating activity did not appreciably inhibit TrxR while another derivative, lacking only the 2-chloroethylating activity, retained its inhibitory potency. Furthermore, in assays measuring TrxR activity in murine cell lysates, a similar pattern of inhibition among these compounds was observed. These data contrast with previous studies demonstrating that glutathione reductase, another enzyme that relies on cysteine-mediated redox chemistry, was not inhibited by methylcarbamoylating agents when measured in cell lysates. Mass spectrometry of Laromustine-treated enzyme revealed significant carbamoylation of TrxR, albeit not on known catalytically active residues. However, there was no evidence of 2-chloroethylation anywhere on the protein. The inhibition of TrxR is likely to contribute to the cytotoxic, anticancer mechanism of action for Laromustine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thioredoxin reductase is inhibited by the carbamoylating activity of the anticancer sulfonylhydrazine drug laromustine

et al. 2012

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“…In recent years, an increasing number of TrxR inhibitors have received attention and have eventually been demonstrated as effective [7,[27][28][29] ; Ethaselen is one promising, potent candidate [26] . However, to the best of our knowledge, no studies have investigated the quantitative relationship between Ethaselen administration and tumor eradication, let alone possible models based on the complicated process and mechanism of Ethaselen action and the TrxR signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Dose-biomarker-response modeling of the anticancer effect of ethaselen in a human non-small cell lung cancer xenograft mouse model

et al. 2016

Acta Pharmacol Sin

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Thioredoxin reductase (TrxR) is a component of several redox-sensitive signaling cascades that mediate important biological processes such as cell survival, maturation, growth, migration and inhibition of apoptosis. The expression levels of TrxR1 in some human carcinoma cell lines are nearly 10 times higher than those in normal cells. Ethaselen is a novel antitumor candidate that exerts potent inhibition on non-small cell lung cancer (NSCLC) by targeting TrxR. In this study we explored the relationship between the ethaselen dose and TrxR activity level and the relationship between TrxR degradation and tumor apoptosis in a human lung carcinoma A549 xenograft model. BALB/c nude mice implanted with human NSCLC cell line A54 were administered ethaselen (36, 72, 108 mg·kg -1 ·d -1 , ig) or vehicle for 10 d. The tumor size and TrxR activity levels in tumor tissues were daily recorded and detected. Based on the experimental data, NONMEM 7.2 was used to develop an integrated dose-biomarker-response model for describing the quantitative relationship between ethaselen dose and tumor eradication effects. The time course of TrxR activity levels was modeled using an indirect response model (IDR model), in which the influence of the tumor growth rates on K in with the linear correction factor γ1 (0.021 d/mm). The drug binding-inhibition effects on K out was described using a sigmoidal E max model with S max (5.95), SC 50 (136 mg/kg) and Hill's coefficient γ2 (2.29). The influence of TrxR activity inhibition on tumor eradication was characterized by an E max model with an E max (130 mm 3 /d) and EC 50 (0.0676). This model was further validated using a visual predictive check (VPC) and was used to predict the efficacy of different doses. In conclusion, the properties and characteristics of ethaselen acting on TrxR degradation and subsequently resulting in tumor apoptosis are characterized by the IDR model and integrated dose-biomarker-response model with high goodness-offit and great predicative ability. This approach shed new light on the detailed processes and mechanism of ethaselen action and may offer a valuable reference for an appropriate dosing regimen for use in further clinical applications.

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“…Besides, TrxRs from different organisms such as Escherichia coli , Mycobacterium leprae , Plasmodium falciparum , Drosophila melanogaster , and human show a surprising diversity in the reduction mechanism. The significant species difference provides the possibility to develop specific TrxR inhibitors for chemotherapeuty 4, 5. In recent years, extensive efforts have been made to develop TrxR inhibitors.…”

Section: Introductionmentioning

confidence: 99%

3‐Nitro‐2H‐chromenes as a New Class of Inhibitors against Thioredoxin Reductase and Proliferation of Cancer Cells

Xiao

Liang

Chen

et al. 2012

Archiv der Pharmazie

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A series of 3-nitrochromenes were designed and synthesized. These compounds showed good inhibitory activity against thioredoxin reductase (TrxR) and the proliferation of A549 cancer cells. The structure-activity relationship analysis indicates that the 3-nitrochromene scaffold is the crucial pharmacophore for achieving good inhibitory activity. The bromo-substitutions at the 6- and 8-position of 3-nitrochromene significantly increase the inhibitory activity.

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Targeting Thioredoxin Reductase: Anticancer Agents and Chemopreventive Compounds

Cited by 13 publications

References 77 publications

Thioredoxin reductase is inhibited by the carbamoylating activity of the anticancer sulfonylhydrazine drug laromustine

Thioredoxin reductase is inhibited by the carbamoylating activity of the anticancer sulfonylhydrazine drug laromustine

Dose-biomarker-response modeling of the anticancer effect of ethaselen in a human non-small cell lung cancer xenograft mouse model

3‐Nitro‐2H‐chromenes as a New Class of Inhibitors against Thioredoxin Reductase and Proliferation of Cancer Cells

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