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The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice
Marielle Breau, … , Fatima Mechta-Grigoriou, Serge Adnot
Marielle Breau, … , Fatima Mechta-Grigoriou, Serge Adnot
Published October 3, 2019
Citation Information: JCI Insight. 2019;4(19):e127647. https://doi.org/10.1172/jci.insight.127647.
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Research Article Oncology Pulmonology

The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice

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Abstract

Oxidative stress is a major contributor to chronic lung diseases. Antioxidants such as N-acetylcysteine (NAC) are broadly viewed as protective molecules that prevent the mutagenic effects of reactive oxygen species. Antioxidants may, however, increase the risk of some forms of cancer and accelerate lung cancer progression in murine models. Here, we investigated chronic NAC treatment in aging mice displaying lung oxidative stress and cell senescence due to inactivation of the transcription factor JunD, which is downregulated in diseased human lungs. NAC treatment decreased lung oxidative damage and cell senescence and protected from lung emphysema but concomitantly induced the development of lung adenocarcinoma in 50% of JunD-deficient mice and 10% of aged control mice. This finding constitutes the first evidence to our knowledge of a carcinogenic effect of antioxidant therapy in the lungs of aged mice with chronic lung oxidative stress and warrants the utmost caution when considering the therapeutic use of antioxidants.

Authors

Marielle Breau, Amal Houssaini, Larissa Lipskaia, Shariq Abid, Emmanuelle Born, Elisabeth Marcos, Gabor Czibik, Aya Attwe, Delphine Beaulieu, Alberta Palazzo, Jean-Michel Flaman, Brigitte Bourachot, Guillaume Collin, Jeanne Tran Van Nhieu, David Bernard, Fatima Mechta-Grigoriou, Serge Adnot

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Figure 5

Inactivation of JunD leads to cell senescence: effects of antioxidant treatment.

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Inactivation of JunD leads to cell senescence: effects of antioxidant tr...
(A) Primary mouse embryonic fibroblasts were infected with control (sh-SCB) or with 2 JunD-targeting (sh-JunD) shRNA retroviral vectors. RNAs were prepared and reverse transcribed, and the JunD transcripts were quantified by qPCR. Results were normalized to the GAPDH transcript level. Graph shows results from 4 separate experiments. (B and C) Cells treated with 1 mM NAC or 0.1 mM β-mercaptoethanol were fixed and stained using crystal violet or were stained for SA-β-Gal activity. The number of SA-β-Gal–positive cells was then counted in each condition. Treatment with NAC or β-mercaptoethanol considerably decreased the number of senescent cells induced by JunD inactivation and increased the number of proliferating cells. Results are individual values and means. P values were calculated using 2-way ANOVA with Bonferroni’s post hoc test. ***P < 0.001; **P < 0.01.

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