Prodrugs Bioactivated to Quinones Target NF-κB and Multiple Protein Networks: Identification of the Quinonome
| Autor: | Emily N. Pierce, Vladislav A. Litosh, Gregory R. J. Thatcher, Yue-Ting Wang, Marton I. Siklos, Sujeewa C. Piyankarage, Tareisha L. Dunlap |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proteomics NF-E2-Related Factor 2 Toxicology Mass Spectrometry Article Activation Metabolic 03 medical and health sciences chemistry.chemical_compound Humans Prodrugs Heat shock Chemistry Drug discovery NF-kappa B Quinones General Medicine Prodrug NFKB1 Quinone methide Transport protein 030104 developmental biology Biochemistry Quantum Theory HT29 Cells Drug metabolism |
| Zdroj: | Chemical research in toxicology. 29(7) |
| ISSN: | 1520-5010 |
| Popis: | Electrophilic reactive intermediates resulting from drug metabolism have been associated with toxicity and off-target effects and in some drug discovery programs trigger NO-GO decisions. Many botanicals and dietary supplements are replete with such reactive electrophiles, notably Michael acceptors, which have been demonstrated to elicit chemo-preventive mechanisms; and Michael acceptors are gaining regulatory approval as contemporary cancer therapeutics. Identifying protein targets of these electrophiles is central to understanding potential therapeutic benefit and toxicity risk. NO-donating NSAID prodrugs (NO-NSAIDs) have been the focus of extensive clinical and preclinical studies in inflammation and cancer chemoprevention and therapy: a subset exemplified by pNO-ASA, induces chemopreventive mechanisms following bioactivation to an electrophilic quinone methide (QM) Michael acceptor. Having previously shown that these NO-independent, QM-donors activated Nrf2 via covalent modification of Keap-1, we demonstrate that components of canonical NF-κB signaling are also targets, leading to the inhibition of NF-κB signaling. Combining bio-orthogonal probes of QM-donor ASA prodrugs with mass spectrometric proteomics and pathway analysis, we proceeded to characterize the quinonome: the protein cellular targets of QM-modification by pNO-ASA and its ASA pro-drug congeners. Further comparison was made using a biorthogonal probe of the “bare-bones”, Michael acceptor, and clinical anti-inflammatory agent, dimethyl fumarate, which we have shown to inhibit NF-κB signaling. Identified quinonome pathways include post-translational protein folding, cell-death regulation, protein transport, and glycolysis; and identified proteins included multiple heat shock elements, the latter functionally confirmed by demonstrating activation of heat shock response. |
| Databáze: | OpenAIRE |
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