Document Detail


Quinone-induced activation of Keap1/Nrf2 signaling by aspirin prodrugs masquerading as nitric oxide.
MedLine Citation:
PMID:  23035985     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The promising therapeutic potential of the NO-donating hybrid aspirin prodrugs (NO-ASA) includes induction of chemopreventive mechanisms and has been reported in almost 100 publications. One example, NCX-4040 (pNO-ASA), is bioactivated by esterase to a quinone methide (QM) electrophile. In cell cultures, pNO-ASA and QM-donating X-ASA prodrugs that cannot release NO rapidly depleted intracellular GSH and caused DNA damage; however, induction of Nrf2 signaling elicited cellular defense mechanisms including upregulation of NAD(P)H:quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase (GCL). In HepG2 cells, the "NO-specific" 4,5-diaminofluorescein reporter, DAF-DA, responded to NO-ASA and X-ASA, with QM-induced oxidative stress masquerading as NO. LC-MS/MS analysis demonstrated efficient alkylation of Cys residues of proteins including glutathione-S-transferase-P1 (GST-P1) and Kelch-like ECH-associated protein 1 (Keap1). Evidence was obtained for alkylation of Keap1 Cys residues associated with Nrf2 translocation to the nucleus, nuclear translocation of Nrf2, activation of antioxidant response element (ARE), and upregulation of cytoprotective target genes. At least in cell culture, pNO-ASA acts as a QM donor, bioactivated by cellular esterase activity to release salicylates, NO(3)(-), and an electrophilic QM. Finally, two novel aspirin prodrugs were synthesized, both potent activators of ARE, designed to release only the QM and salicylates on bioactivation. Current interest in electrophilic drugs acting via Nrf2 signaling suggests that QM-donating hybrid drugs can be designed as informative chemical probes in drug discovery.
Authors:
Tareisha Dunlap; Sujeewa C Piyankarage; Gihani T Wijewickrama; Samer Abdul-Hay; Michael Vanni; Vladislav Litosh; Jia Luo; Gregory R J Thatcher
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-18
Journal Detail:
Title:  Chemical research in toxicology     Volume:  25     ISSN:  1520-5010     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-17     Completed Date:  2013-05-16     Revised Date:  2014-01-24    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2725-36     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Aspirin / analogs & derivatives*,  pharmacology*
Cell Line, Tumor
DNA Damage
Glutathione / metabolism
Glutathione S-Transferase pi / metabolism
Humans
Indolequinones / metabolism*
Intracellular Signaling Peptides and Proteins / metabolism*
Mice
NAD(P)H Dehydrogenase (Quinone) / metabolism
NF-E2-Related Factor 2 / metabolism*
Nitric Oxide / metabolism
Prodrugs / pharmacology*
Grant Support
ID/Acronym/Agency:
CA102590/CA/NCI NIH HHS; R01 CA102590/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Indolequinones; 0/Intracellular Signaling Peptides and Proteins; 0/KEAP1 protein, human; 0/NF-E2-Related Factor 2; 0/NFE2L2 protein, human; 0/Prodrugs; 138230-21-4/quinone methide; 31C4KY9ESH/Nitric Oxide; EC 1.6.5.2/NAD(P)H Dehydrogenase (Quinone); EC 1.6.5.2/Nqo1 protein, mouse; EC 2.5.1.18/Glutathione S-Transferase pi; GAN16C9B8O/Glutathione; R16CO5Y76E/Aspirin
Comments/Corrections

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