N6-isopentenyladenosine and analogs activate the NRF2-mediated antioxidant response

Redox Biology

卷:2

Loris De Cecco¹  Francesca Colombo²  Alice Dassano²  Tommaso A. Dragani²  Paola Giardullo³  Pierangela Ciuffreda⁴  Enzo Santaniello⁵  Mariateresa Mancuso⁶  Anna Saran⁶ 

[1] Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan I-20133, Italy;

[2] Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan I-20133, Italy;

[3] Department of Radiation Physics, Guglielmo Marconi University, Rome I-00193, Italy;

[4] Dipartimento di Scienze Biomediche e Cliniche “L. Sacco”, Università di Milano, Italy;

[5] Dipartimento di Scienze della Salute, Università di Milano, Milan I-20142, Italy;

[6] Laboratory of Radiation Biology and Biomedicine, ENEA, Casaccia Research Centre, Rome I-00123, Italy;

关键词: Modified nucleosides;    Gene expression;    Reactive oxygen species;    Anti-inflammatory drug;    Pathway analysis;   

DOI  :  10.1016/j.redox.2014.03.001

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown