ArticleChemical research in toxicology2011
Susceptibility of the antioxidant selenoenyzmes thioredoxin reductase and glutathione peroxidase to alkylation-mediated inhibition by anticancer acylfulvenes.
Article in Chemical research in toxicology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 30 citations in OpenAlex.
- The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations.Oncotarget · 2021Article
- A machine learning-based gene signature of response to the novel alkylating agent LP-184 distinguishes its potential tumor indications.BMC bioinformatics · 2021Article
- Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death.Science advances · 2020Article
- A Chemical Proteomic Analysis of Illudin-Interacting Proteins.Chemistry (Weinheim an der Bergstrasse, Germany) · 2019Article
- Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions.Journal of medicinal chemistry · 2017Article
- Cellular Protection of SNAP-25 against Botulinum Neurotoxin/A: Inhibition of Thioredoxin Reductase through a Suicide Substrate Mechanism.Journal of the American Chemical Society · 2016Article
- Improved efficacy of acylfulvene in colon cancer cells when combined with a nuclear excision repair inhibitor.Chemical research in toxicology · 2013Article
- Selenium compounds, apoptosis and other types of cell death: an overview for cancer therapy.International journal of molecular sciences · 2012Review
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Selenium, in the form of selenocysteine, is a critical component of some major redox-regulating enzymes, including thioredoxin reductase (TrxR) and glutathione peroxidase (Gpx). TrxR has emerged as an anticancer target for drug development due to its elevated expression level in many aggressive human tumors. Acylfulvenes (AFs) are semisynthetic derivatives of the natural product illudin S and display improved cytotoxic selectivity profiles. AF and illudin S alkylate cellular macromolecules. Compared to AFs, illudin S more readily reacts with thiol-containing small molecules such as cysteine, glutathione, and cysteine-containing peptides. However, a previous study indicates that the reactivity of AFs and illudin S with glutathione reductase, a thiol-containing enzyme, is inversely correlated with the reactivity toward small molecule thiols. In this study, we investigate mechanistic aspects underlying the enzymatic and cellular effects of the AFs and illudin S on thioredoxin reductase. Both AF and HMAF were found to inhibit mammalian TrxR in the low- to submicromolar range, but illudin S was significantly less potent. TrxR inhibition by AFs was shown to be irreversible, concentration- and time-dependent, and mediated by alkylation of C-terminus active site Sec/Cys residues. In contrast, neither AFs nor illudin S inhibits Gpx, demonstrating that enzyme structure-specific small molecule interactions have a significant influence over the inherent reactivity of the Sec residue. In human cancer cells, TrxR activity can be inhibited by low micromolar concentrations of all three drugs. Finally, it was demonstrated that preconditioning cells by the addition of selenite to the cell culture media results in an enhancement in cell sensitivity toward AFs. These data suggest potential strategies for increasing drug activity by combination treatments that promote selenium enzyme activity.
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