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 4

NAC treatment leads to lung adenocarcinoma development.

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NAC treatment leads to lung adenocarcinoma development. (A) Lung adenoca...
(A) Lung adenocarcinomas (ADK) as shown on representative micrographs were found in 2 of 15 aged control mice treated with NAC and in 7 of 14 aged JunD–/– mice treated with NAC. Fractions on the top of the bars indicate the number of mice with ADK in each group. *P < 0.05 comparing mice treated with NAC with mice not treated with NAC, using the χ2 test. (B) Representative photomicrographs of lung adenocarcinoma. (C) Images of the same area stained with hematoxylin and eosin and Sirius Red. (D) Arrowheads showing vacuolated tumor cells in adenocarcinoma (original magnification, ×40). (E) Percentage of Ki67-positive cells in normal lung tissue (left part of the figure) and in adenocarcinoma tissue (ADK) from aged control and JunD–/– mice. Data represent median (interquartile range); bars represent extreme values. n = 8 animal per group for young mice, 2 animals for control + NAC with ADK and 4 for JunD–/– + NAC with ADK. (F) Photomicrographs showing numerous p16- and p21-positive senescent cells in the lung around, but not within, the tumor. In contrast, Ki67-positive cells were abundant within the tumor but absent from the surrounding lung tissue. (G) Lung area of inflammatory cell infiltrates in young and aged mice. Representative images are shown in the right panel. Values represent median (interquartile range). Bars represent extreme values. n = 8 animals per group. P values were calculated using 2-way ANOVA with Bonferroni’s post hoc test. ***P < 0.001; **P < 0.01.