Evaluation ofN-acetyl-S-(p-chlorophenylcarbamoyl)cysteine as an irreversible inhibitor of mammalian thioredoxin reductase1

Chen, Wei; Jiang, Zhiming; Lin, Nengming; Zheng, Zhong; Chen, Zhongjian; Zhang, Xiaoying; Guan, Xiaoxu

doi:10.3109/14756366.2015.1016512

Cited by 6 publications

(4 citation statements)

References 24 publications

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“…It has been shown that recombinant mutant TrxR containing cysteine instead of selenocysteine in the active centre showed a 100 times lower catalytic constant value in comparison to the wild type Sec-containing enzyme. It was also observed that the substitution of redox inactive serine in place of selenocysteine completely inactivates the enzyme 12,13 .…”

Section: Structure and Function Of The Thioredoxin-dependent Systemmentioning

confidence: 99%

Thioredoxin-dependent system. Application of inhibitors

Jastrząb

Skrzydlewska

2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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One of the systems responsible for maintaining cellular redox homeostasis is the thioredoxin-dependent system. An equally important function of this system is the regulation of the expression of many proteins by the transcription factor NF-jB or the apoptosis regulating kinase (ASK-1). Since it has been shown that the Trx-dependent system can contribute to both the enhancement of tumour angiogenesis and growth as well as apoptosis of neoplastic cells, the search for compounds that inhibit the level/activity of Trx and/ or TrxR and thus modulate the course of the neoplastic process is ongoing. It has been shown that many naturally occurring polyphenolic compounds inactivate elements of the thioredoxin system. In addition, the effectiveness of Trx is inhibited by imidazole derivatives, while the activity of TrxR is reduced by transition metal ions complexes, dinitrohalobenzene derivatives, Michael acceptors, nitrosourea and ebselen. In addition, research is ongoing to identify new selective Trx/TrxR inhibitors.

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Section: Structure and Function Of The Thioredoxin-dependent Systemmentioning

confidence: 99%

Thioredoxin-dependent system. Application of inhibitors

Jastrząb

Skrzydlewska

2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…ROS generation by NACC could be one of the factors responsible for the disruption of mitochondrial membrane potential in the melanoma cells. Recently, we found that NACC is an irreversible inhibitor which is capable of inhibiting intracellular thioredoxin reductase (TrxR) in UACC-62 cells (38). It was reported by Fang et al (39) that TrxR inhibitor is able to induce ROS production in the presence of oxygen.…”

Section: Discussionmentioning

confidence: 89%

N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine induces mitochondrial-mediated apoptosis and suppresses migration in melanoma cells

Chen

Jiang

Zhang³

et al. 2015

Oncology Reports

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We previously reported that N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine (NACC) induces apoptosis in human melanoma UACC-62 cells. In the present study, the molecular mechanism of NACC‑induced apoptosis in melanoma cells was investigated. Briefly, the apoptosis triggered by NACC was confirmed in UACC‑62 cells for shorter treatment periods. Increased activities of caspase‑3 and caspase‑9 but not caspase‑8 were observed in the cell lysates. Western blotting showed that the pro‑apoptotic protein Bax was upregulated and the anti‑apoptotic protein Mcl‑1 was downregulated and cytochrome c (Cyto c) was released into the cytosol. Flow cytometric analysis demonstrated that NACC induced significant mitochondrial membrane potential disruption. Significant increases in the generation of reactive oxygen species (ROS) and cytosolic calcium elevation were also observed. However, opening of the mitochondrial permeability transition pore which could be involved in Cyto c leakage from mitochondria was found to be unaffected by NACC. Taken together, all the results presented in this study including apoptotic induction, activation of the caspase‑3 and ‑9 cascade, upregulation of Bax, downregulation of Mcl‑1, Cyto c release from the mitochondria, mitochondrial membrane potential depletion, ROS production and cytosolic calcium elevation demonstrated that NACC triggered apoptosis in the UACC‑62 cells via the mitochondrial‑dependent pathway. Melanoma is well‑known as an aggressive and highly metastatic disease. In this study, we also investigated the effects of NACC on the migration of UACC‑62 cells using the xCELLigence system. The results revealed that in vitro NACC is capable of inhibiting the migration of melanoma cells.

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“…yGR samples for mass spectrometric analysis were prepared as described earlier for thioredoxin reductase mass spectrometric analysis 22 with minor modifications. In brief, 8.0 µg reduced yGR (NADPH-treated) was treated with 0.2 mM BITC in the presence of 0.2 mM NADPH in PE buffer for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Characterisation of naturally occurring isothiocyanates as glutathione reductase inhibitors

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Glutathione reductase (GR), an essential antioxidant enzyme against oxidative stress, has become an attractive drug target for the development of anticancer and antimalarial drugs. In this regard, we evaluated the naturally occurring isothiocyanates as promising GR inhibitors and elucidated the mechanism of action. It was found that benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) inhibited yeast GR (yGR) and human GR (hGR) in a time-and concentration-dependent manner. The K i and k inact of BITC against yGR were determined to be 259.87 mM and 0.0266 min À1 , respectively. The GR inhibition occurred only in the presence of NADPH and persisted after extensive dialysis. The tandem mass spectrometric analysis revealed that Cys 61 rather than Cys 66 at the active site of yGR was mono-benzyl thiocarbamoylated by BITC. Inhibition of intracellular GR by BITC and PEITC in cultured cancer cells was also observed. BITC and PEITC were evaluated as competitive and irreversible inhibitors of GR.

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Evaluation ofN-acetyl-S-(p-chlorophenylcarbamoyl)cysteine as an irreversible inhibitor of mammalian thioredoxin reductase1

Cited by 6 publications

References 24 publications

Thioredoxin-dependent system. Application of inhibitors

Thioredoxin-dependent system. Application of inhibitors

N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine induces mitochondrial-mediated apoptosis and suppresses migration in melanoma cells

Characterisation of naturally occurring isothiocyanates as glutathione reductase inhibitors

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