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.

N(6)-isopentenyladenosine and analogs activate the NRF2-mediated antioxidant response / A. Dassano, M. Mancuso, P. Giardullo, L. De Cecco, P. Ciuffreda, E. Santaniello, A. Saran, T.A. Dragani, F. Colombo. - In: REDOX BIOLOGY. - ISSN 2213-2317. - 2:1(2014 Mar), pp. 580-589.

N(6)-isopentenyladenosine and analogs activate the NRF2-mediated antioxidant response

P. Ciuffreda;E. Santaniello;
2014

Abstract

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.
anti-inflammatory drug; gene expression; modified nucleosides; pathway analysis; reactive oxygen species; allyl6A; N6-allyladenosine; benzyl6A; N6-benzyladenosine; butyl6A; N6-butyladenosine; i6A; N6-isopentenyladenosine
Settore BIO/10 - Biochimica
mar-2014
Article (author)
File in questo prodotto:
File Dimensione Formato  
redox-biology2014.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.47 MB
Formato Adobe PDF
1.47 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/234369
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 18
social impact