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

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 2

Aging and JunD deficiency lead to lung oxidative stress in mice: effect of NAC treatment.

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Aging and JunD deficiency lead to lung oxidative stress in mice: effect ...
JunD–/– and littermate control mice were studied at 4 (young) and 12–18 (aged) months of age. (A) Protein levels of JunD and Nrf2 measured in lung homogenates from corresponding mouse groups by Western blot analysis. Data are individual values and means. Representative gels for JunD and β-actin (top panels) and NRF2 and β-actin (bottom panels) for controls (CTL) and JunD–/– mouse lungs. (B) Representative micrographs showing lung localization of JunD cells stained for β-galactosidase activity at pH 7.4 (due to lacZ gene insertion into the JunD locus). (C) Quantification of manganese superoxide dismutase (mnSOD), NAD(P)H quinone dehydrogenase 1 (NQO1), and heme oxygenase (Hmox) mRNA levels, by RT-qPCR in lung homogenates from the corresponding mouse groups. Data are shown as median (interquartile range) for 7 (JunD–/–) to 10 (control) animals per group. Bars represent extreme values. (D) Quantification of ROS production by determination of DCFH-DA (a cell-permeant fluorogenic dye that emits fluorescence when oxidized by ROS) in cultured pulmonary-artery smooth muscle cells from JunD–/– and control mice. Results are individual values and means. (E) Quantification of lung lipid peroxidation by 4-HNE staining activity in the different mouse groups. Representative micrographs are shown on the right. (F) Quantification of lung DNA oxidation by determination of the percentage of 8-oxoguanine–positive cells in the different mouse groups. Representative micrographs are shown on the right. Stained cells are indicated by red arrows. 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; *P < 0.05.