Lung cancer is the leading cause of
cancer related deaths worldwide. The present study investigated the effects of
naproxen (
NSAID) on
lung adenocarcinoma in spontaneous
lung cancer mouse model. Six-week-old transgenic KrasG12V mice (n = 20; male + female) were fed modified AIN-76A diets containing
naproxen (0/400 ppm) for 30 wk and euthanized at 36 wk of age. Lungs were evaluated for
tumor incidence, multiplicity, and histopathological stage (
adenoma and
adenocarcinoma). Lung
tumors were noticeable as early as 12 wk of age exclusively in the KrasG12V mice. By 36 wk age, 100% of KrasG12V mice on control diet developed lung
tumors, mostly
adenocarcinomas. KrasG12V mice fed control diet developed 19.8 ± 0.96 (Mean ± SEM) lung
tumors (2.5 ± 0.3
adenoma, 17.3 ± 0.7
adenocarcinoma). Administration of
naproxen (400 ppm) inhibited lung
tumor multiplicity by ∼52% (9.4 ± 0.85; P < 0001) and
adenocarcinoma by ∼64% (6.1 ± 0.6; P < 0001), compared with control-diet-fed mice. However, no significant difference was observed in the number of
adenomas in either diet, suggesting that
naproxen was more effective in inhibiting
tumor progression to
adenocarcinoma.
Biomarker analysis showed significantly reduced
inflammation (COX-2, IL-10), reduced
tumor cell proliferation (
PCNA,
cyclin D1), and increased apoptosis (p21, caspase-3) in the lung
tumors exposed to
naproxen. Decreased serum levels of
PGE2 and CXCR4 were observed in
naproxen diet fed KrasG12V mice. Gene expression analysis of
tumors revealed a significant increase in
cytokine modulated genes (H2-Aa, H2-Ab1, Clu), which known to further modulate the
cytokine signaling pathways. Overall, the results suggest a chemopreventive role of
naproxen in inhibiting spontaneous
lung adenocarcinoma formation in KrasG12V mice.