Metal- and Semimetal-Containing Inhibitors of Thioredoxin Reductase as Anticancer Agents

Gandin, Valentina; Fernandes, Aristi P.

doi:10.3390/molecules200712732

Cited by 59 publications

(50 citation statements)

References 97 publications

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“…Since the intracellular redox conditions seem to play a key role in the establishment of the chronic phase of HCV infection, we decided to evaluate whether the oxidative stress could reactivate HCV replication in chronically infected cells. For this reason, a chemical treatment with auranofin (Au), a well-known prooxidant drug [39] that induces ROS production in infected cells [40,41], was used. In our experimental model, treatment with Au (200 nM) for 48 hrs was able to induce an increment of intracellular ROS levels by twofold, either in uninfected (CTR) or in HCV-infected cells (Figure 5(a)).…”

Section: Auranofin-induced Oxidative Stress Leads To Increasedmentioning

confidence: 99%

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Anticoli

Amatore

Matarrese

et al. 2019

Oxidative Medicine and Cellular Longevity

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Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with chronic HCV infection are not fully understood yet, mainly due to the lack of an in vitro system able to recapitulate the stages of infection in vivo. Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is still not clear. We set up an in vitro system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection.

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Section: Auranofin-induced Oxidative Stress Leads To Increasedmentioning

confidence: 99%

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Anticoli

Amatore

Matarrese

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…There are increasing metal complexes, especially the gold and platinum complexes, which have been reported as TrxR inhibitors . In this section, we reviewed the gold‐containing inhibitors first, and then platinum‐containing complexes.…”

Section: Thioredoxin Reductase Inhibitorsmentioning

confidence: 99%

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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“…[240] The Cterminal sequence containing the seleno-cysteine (Sec) residue has been identified as reactive towards several compounds, and such interaction was shown to inhibit the activity of the protein. Although cisplatin and gold-based (Au(I) and Au(III)) complexes have been described to inhibit TrxR using in vitro assays, [248][249][250][251][252][253][254][255][256][257][258] The results suggested that arsenic trioxide binds to both sulfur and selenium in the C-terminal motif GlyCysSecGly of the protein, and although precise identification of the coordination sites was not possible, the N-terminal sequence was also found to participate in the reaction with As. [263] However, it is worth mentioning that in this report, no evidence for the selenium isotopic pattern on the peptide fragment bound to arsenic has been provided.…”

Section: Seleno-enzymesmentioning

confidence: 99%

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

Wenzel

Casini

2017

Coordination Chemistry Reviews

107

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Metal-based compounds form a promising class of therapeutic agents, whose mechanisms of action still need to be elucidated, and that are in general prone to undergo extensive speciation in physiological environment. Thus, determination of the fate of the metal compounds in complex biological systems, contributing to their overall pharmacological and toxicological profiles, is important to develop more rationalised and targeted metal-based drugs. To these aims, a number of spectroscopic and biophysical methods, as well as analytical techniques, are nowadays extensively applied to study the reactivity of metal complexes with different biomolecules (e.g. nucleic acids, proteins, buffer components). Among the various techniques, molecular mass spectrometry (MS) has emerged in the last decade as a major tool to characterise the interactions of metallodrugs at a molecular level. In this review, we present an overview of the information available on the reactivity of various families of therapeutic metallodrugs (mainly anticancer compounds based on Pt, Ru, Au and As) with biomolecules studied by different MS techniques, including high-resolution ESI-, MALDI-and ion mobility-MS among others. Representative examples on the potential of the MS approach to study non-covalent interactions are also discussed. The review is organized to present results obtained on samples with different degrees of complexity, from the interactions of metal compounds with small model nucleophiles (amino acids and nucleobases), model peptides/oligonucleotides, target proteins/nucleic acids, to the analysis of serum, cell extracts and tissue samples. The latter requiring combination of proteomic methods with advanced MS techniques. Correlations between molecular reactivity of metallodrugs and biological activity are hard to establish, but differences in the reactivity of metallodrugs to biomolecules and their different adducts, as revealed by MS methods, may indicate differences in their modes of action. Overall, the knowledge offered by MS methods on metallodrugs speciation is invaluable to establish new rules and define new trends in the periodic table aimed at rationalizing the behavior of metal compounds in complex living systems. Keywordsmetal-based drugs; proteins; nucleic acids; mass spectrometry; metallomics. Corresponding Author Angela Casini Corresponding Author's InstitutionCardiff University To view all the submission files, including those not included in the PDF, click on the manuscript title on your EVISE Homepage, then click 'Download zip file'. Order of Authors 1 Answers to Reviewers Reviewer 1 The authors have made some effort to answer suggestions and the manuscript is improved. Since it is a review, there is, strictly, no new information but nevertheless the compilation of data and references could be useful.Answer: no further comments. Liu et al." in place of "Lu et al." iv) Some symbols in the PDF file are not correctly displayed. Reviewer Answer:We have inserted all the minor modifications requested by this rev...

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Metal- and Semimetal-Containing Inhibitors of Thioredoxin Reductase as Anticancer Agents

Cited by 59 publications

References 97 publications

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

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

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

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