Quinone-Induced Activation of Keap1/Nrf2 Signaling by Aspirin Prodrugs Masquerading as Nitric Oxide

Dunlap, Tareisha; Piyankarage, Sujeewa C.; Wijewickrama, Gihani T.; Abdul-Hay, Samer O.; Vanni, Michael; Litosh, Vladislav A.; Luo, Jia; Thatcher, Gregory R. J.

doi:10.1021/tx3003609

Cited by 22 publications

(29 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23 Inhibition of β -catenin signaling by NO-ASA and of β -catenin’s ability to regulate NF- κ B binding to DNA has previously been reported in human colon cancer cells. 50,51 Mechanisms involving the covalent modification of Cys residues of p65 leading to decreased DNA/NF- κ B binding have also been proposed.…”

Section: Discussionmentioning

confidence: 94%

“…23 The reported biological activity of p NO-ASA has also been linked to NF- κ B pathway inhibition, including in colon cancer cell lines; therefore covalent modification of proteins in the NF- κ B pathway is a likely mechanism for p NO-ASA and for other QM-donor compounds such as p Br-ASA. The QM-donor ASA hybrids were studied in HT-29 colon cancer cells transiently transfected with NF- κ B-luciferase.…”

Section: Resultsmentioning

confidence: 99%

“…22,57 As we have emphasized previously, depletion of cellular glutathione is a key contributor to biological activity. 10,14,16 Under these conditions, oxidation of protein thiols in addition to direct alkylation will likely increase the extent of protein modification and therefore amplify the perturbation of protein networks. The challenge in these studies on therapeutic electrophiles will be to define the differences in cellular targets that might bias toward toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 We demonstrated that this spectrum of activity could be replicated in cell cultures by congeners ( p X-ASA) not containing an NO-donating group and was the result of bioactivation to a Michael acceptor quinone methide (QM). 10,14–16 Alternative ASA and NSAID hybrid molecules, devoid of any putative NO-donating capacity, have been developed and validated in animal models: for example, phospho-aspirins have been reported to have an improved gastrointestinal toxicity profile relative to ASA and have been studied in cancer cell lines and xenografts. 17–19 A recent publication on the quinone-donor aspirin, p NO-ASA, reported antiproliferative effects in TNBC xenografts, proposed to be mediated through inhibition of the NF-kB pathway and induction of ROS.…”

Section: Introductionmentioning

confidence: 99%

“…We have shown that p NO-ASA and p X-ASA covalently modify the Cys residues of Keap1, leading to activation of Nrf2 and induction of cytoprotective and detoxifying enzymes, considered important in chemoprevention. 16,23 Similarly, the QM from p NO-ASA and p X-ASA is likely to react with a variety of other proteins, via covalent protein modification, which may play crucial physiological roles including in cell viability and apoptosis. This study is focused on identifying the quinonome via a proteomic pathway analysis.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Prodrugs Bioactivated to Quinones Target NF-κB and Multiple Protein Networks: Identification of the Quinonome

Pierce

Piyankarage

Dunlap

et al. 2016

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%