Inhibition of thioredoxin reductase by lanthanum chloride

Citta, Anna; Folda, Alessandra; Scutari, Guido; Cesaro, Luca; Bindoli, Alberto; Rigobello, Maria Pia

doi:10.1016/j.jinorgbio.2012.08.014

Cited by 14 publications

(9 citation statements)

References 62 publications

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“…Since thioredoxin reductase-1 (TrxR-1) is the enzyme responsible for reduction of TRX-1 in the cytoplasm 22 23 , we further investigated whether TrxR-1 inhibition, and the consequent redox shift of TRX-1 from its reduced to oxidized state, could prevent the APO-induced NF-κB over activation. In fact, LPS-stimulated RAW264.7-Luc cells treated with APO and pre-incubated with auranofin (AUR, which blocks the selenocysteine 496 of TrxR-1 22 ) or lanthanum chloride (LaCl 3 , which inhibits the NADPH interaction site of TrxR-1 23 ), showed a markedly lower NF-κB activation than cells treated with APO alone ( Fig. 4A,B ).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, some studies have shown an association between Nox2 deficiency and an altered Ca 2+ influx 33 34 35 . In this regard, LaCl 3 , in addition to its role inhibiting TrxR-1, is also able to block Ca 2+ channels 23 and to impair the binding of LPS to monocytes 36 . Since, it was verified that LaCl 3 increased survival rates of APO-treated mice submitted to CLP, we cannot exclude the additional protective effect of in vivo Ca 2+ blockade in endothelial cells or platelets, which could prevent vascular dysfunction in sepsis.…”

Section: Discussionmentioning

confidence: 99%

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Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state

Trevelin

Santos

Ferreira

et al. 2016

Sci Rep

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The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB. The NF-κB overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (CGD) and sepsis. In fact, TrxR-1 inhibition prevents nuclear accumulation of TRX-1 and LPS-stimulated hyperproduction of tumor-necrosis-factor-(TNF)-α by monocytes and neutrophils purified from blood of CGD patients, who have deficient Nox2 activity. TrxR-1 inhibitors, either lanthanum chloride (LaCl3) or auranofin (AUR), also increase survival rates of mice undergoing cecal-ligation-and-puncture-(CLP). Therefore, our results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to hyperinflammation in CGD and in septic patients. Additionally, we suggest that TrxR-1 inhibitors could be potential drugs to treat patients with sepsis, particularly in those with CGD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state

Trevelin

Santos

Ferreira

et al. 2016

Sci Rep

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“…Lanthanum chloride (LaCl 3 ) ( 180 , Figure ) was reported by Bindoli and co‐workers, which is a good inhibitor of both the cytosolic TrxR1 and mitochondrial TrxR2 with IC 50 values of 1.75 and 7.46 μM, respectively. In A2780 cells, lanthanum ions showed a noticeable inhibition of TrxR indicating the ability of lanthanum ion to reach the active site of the TrxR even in a cellular setting . Gandin et al.…”

Section: Thioredoxin Reductase Inhibitorsmentioning

confidence: 98%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

133

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Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

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“…12 Although the cytotoxic action of lanthanide complexes is typically attributed to their interactions with DNA, other mechanisms have been proposed: Pr 3+ , La 3+ , and Nd 3+ were found to inhibit calcium transport in mitochondria (owing to similar ionic radii), 16 and Yb-OEP-treated cells (Scheme 1) were found to undergo endoplasmic reticulum stress pathway-mediated apoptosis, with IC 50 values in the sub-micromolar range. 17 Other notable mechanisms include the inhibition of thioredoxin reductase 18 and targeting of the glutathione-independent lipoate reduction pathway by gadolinium(III) texaphryin (MGd, Xcytrin®) (Scheme 1), 19 subsequently inhibiting cancer cell DNA replication, repair, and inducing oxidative stress.…”

Section: Cytotoxic Agents and Inhibitorsmentioning

confidence: 99%

Lanthanides: Applications in Cancer Diagnosis and Therapy

2016

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Lanthanide complexes are of increasing importance in cancer diagnosis and therapy, owing to the versatile chemical and magnetic properties of the lanthanide-ion 4f electronic configuration. Following the first implementation of gadolinium(III)-based contrast agents in magnetic resonance imaging in the 1980s, lanthanide-based small molecules and nanomaterials have been investigated as cytotoxic agents and inhibitors, in photodynamic therapy, radiation therapy, drug/gene delivery, biosensing, and bioimaging. As the potential utility of lanthanides in these areas continues to increase, this timely perspective of current applications will be useful to medicinal chemists and other investigators interested in the latest developments and trends in this emerging field.

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Inhibition of thioredoxin reductase by lanthanum chloride

Cited by 14 publications

References 62 publications

Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state

Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Lanthanides: Applications in Cancer Diagnosis and Therapy

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