|Title||N6-isopentenyladenosine and analogs activate the NRF2-mediated antioxidant response|
|Publication Type||Articolo su Rivista peer-reviewed|
|Year of Publication||2014|
|Authors||Dassano, A., Mancuso Mariateresa, Giardullo Paola, Cecco L.D., Ciuffreda P., Santaniello E., Saran Anna, Dragani T.A., and Colombo F.|
|Keywords||3 dimethylallyl)adenosine, 6 n (3, 6 n benzyladenosine, adenosine derivative, Administration, analogs and derivatives, animal, animal experiment, animal model, animal tissue, Animals, antiinflammatory activity, antiinflammatory agent, Antioxidant, antioxidant activity, antioxidant responsive element, Antioxidants, article, breast adenocarcinoma, cancer growth, cancer inhibition, Cell Line, cell proliferation, chemically induced, controlled study, disease model, Disease Models, drug effects, Female, Gene expression, gene expression regulation, HL 60 cell line, HL-60 Cells, human, human cell, Humans, Hydrogen Peroxide, in vitro study, in vivo study, inflammation, Isopentenyladenosine, luciferase, luciferase assay, MCF 7 cell line, MCF-7 Cells, metabolism, Mice, mouse, n6 allyladenosine, n6 butyladenosine, Neoplastic, neutrophil, neutrophil chemotaxis, NF-E2-Related Factor 2, NFE2L2 protein, nonhuman, otitis, oxidation reduction reaction, Oxidation-Reduction, Oxidative stress, phorbol 13 acetate 12 myristate, priority journal, protein expression, reactive oxygen metabolite, Reactive Oxygen Species, signal transduction, Tetradecanoylphorbol Acetate, Topical, topical drug administration, transcription factor Nrf2, transcription initiation, treatment response, tumor cell, unclassified drug|
N6-isopentenyladenosine (i6A), a naturally occurring modified nucleoside, inhibits the proliferation of human tumor cell lines in vitro, but its mechanism of action remains unclear. Treatment of MCF7 human breast adenocarcinoma cells with i6A or with three synthetic analogs (allyl6A, benzyl6A, and butyl6A) inhibited growth and altered gene expression. About 60% of the genes that were differentially expressed in response to i6A treatment were also modulated by the analogs, and pathway enrichment analysis identified the NRF2-mediated oxidative stress response as being significantly modulated by all four compounds. Luciferase reporter gene assays in transfected MCF7 cells confirmed that i6A activates the transcription factor NRF2. Assays for cellular production of reactive oxygen species indicated that i6A and analogs had antioxidant effects, reducing basal levels and inhibiting the H2O2- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced production in MCF7 or dHL-60 (HL-60 cells induced to differentiate along the neutrophilic lineage) cell lines, respectively. In vivo, topical application of i6A or benzyl6A to mouse ears prior to TPA stimulation lessened the inflammatory response and significantly reduced the number of infiltrating neutrophils. These results suggest that i6A and analogs trigger a cellular response against oxidative stress and open the possibility of i6A and benzyl6A being used as topical anti-inflammatory drugs. © 2014 The Authors.
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