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

Alice Dassano1, Mariateresa Mancuso2, Paola Giardullo3

  • 1Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan I-20133, Italy.

Redox Biology
|April 2, 2014
PubMed

Insights

N(6)-isopentenyladenosine (i(6)A) and its analogs inhibit tumor cell growth by activating the NRF2 pathway, reducing oxidative stress. These compounds also demonstrate topical anti-inflammatory effects by decreasing neutrophil infiltration.

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Cell Biology

Background:

  • N(6)-isopentenyladenosine (i(6)A) is a natural nucleoside with known anti-proliferative effects on human tumor cell lines.
  • The precise mechanism of action for i(6)A's anti-tumor activity has not been fully elucidated.

Purpose of the Study:

  • To investigate the mechanism of action of i(6)A and its synthetic analogs in inhibiting tumor cell proliferation.
  • To explore the role of the NRF2 pathway and oxidative stress in i(6)A's effects.
  • To evaluate the potential anti-inflammatory properties of i(6)A and its analogs in vivo.

Main Methods:

  • Treatment of MCF7 human breast adenocarcinoma cells with i(6)A and synthetic analogs (allyl(6)A, benzyl(6)A, butyl(6)A).
  • Gene expression analysis and pathway enrichment analysis (NRF2-mediated oxidative stress response).
  • Luciferase reporter gene assays to confirm NRF2 activation.
  • Reactive oxygen species (ROS) assays.
  • In vivo topical application studies on mouse ears followed by TPA stimulation.

Main Results:

  • i(6)A and analogs inhibited MCF7 cell growth and altered gene expression, with significant overlap between compounds.
  • The NRF2-mediated oxidative stress response pathway was modulated by all tested compounds.
  • i(6)A activated NRF2 transcription and exhibited antioxidant effects, reducing basal and induced ROS production.
  • Topical i(6)A and benzyl(6)A reduced TPA-induced inflammation and neutrophil infiltration in mouse ears.

Conclusions:

  • i(6)A and its analogs activate the NRF2 pathway, leading to a cellular response against oxidative stress.
  • These findings suggest a potential therapeutic application for i(6)A and benzyl(6)A as topical anti-inflammatory agents.
Keywords:
Anti-inflammatory drugGene expressionModified nucleosidesPathway analysisReactive oxygen speciesallyl6A, N6-allyladenosinebenzyl6A, N6-benzyladenosinebutyl6A, N6-butyladenosinei6A, N6-isopentenyladenosine

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