Modulation by aspirin and naproxen of nucleotide alterations and tumors in the lung of mice exposed to environmental cigarette smoke since birth

Abstract

Chemoprevention provides an important strategy for cancer control in passive smokers. Due to the crucial role played by smoke-related chronic inflammation in lung carcinogenesis, of special interest are extensively used pharmacological agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs). We evaluated the ability of aspirin and naproxen, inhibitors of both cyclooxygenase-1 and cyclooxygenase -2, to modulate environmental cigarette smoke (ECS)-induced lung carcinogenesis in A/J mice of both genders. Based on a subchronic toxicity study in 180 postweaning mice, we used 1600 mg/kg diet aspirin and 320 mg/kg diet naproxen. In the tumor chemoprevention study, using 320 mice, exposure to ECS started soon after birth and administration of NSAIDs started after weaning. At 10 weeks of life, the NSAIDs did not affect the presence of occult blood in feces. As assessed in a subset of 40 mice, bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine levels were considerably increased in ECS-exposed mice and, irrespective of gender, both NSAIDs remarkably inhibited these nucleotide alterations. After exposure for 4 months followed by 5 months in filtered air, ECS induced a significant increase in the yield of surface lung tumors, the 43.7% of which were adenomas and the 56.3% were adenocarcinomas. Oct-4 (octamer-binding transcription factor 4), a marker of cell stemness, was detected in some adenocarcinoma cells. The NAIDs attenuated the yield of lung tumors, but prevention of ECS-induced lung adenomas was statistically significant only in female mice treated with aspirin, which supports a role for estrogens in ECS-related lung carcinogenesis and highlights the antiestrogenic properties of NSAIDs.

Figure 1.

Body weights (means ± SE), measured at monthly intervals during the first 9 months of life, of male and female A/J mice, either sham-exposed (empty circles) or exposed to ECS during the first 4 months (full circles) or ECS-exposed and treated with AsA (triangles) or naproxen (squares) from weaning until the end of the experiment.

Figure 2.

Examples of histopathological appearance of adenomas and adenocarcinomas detected on the lung surface, and their incidence and multiplicity in 9-month old A/J mice, either males (M) or females (F). The mice were either sham-exposed (35M and 33 F) or exposed to ECS during the first 4 months, starting at birth (35M and 35 F), or ECS-exposed and treated with either AsA (35M and 34 F) or naproxen (35M and 35 F) from weaning until the end of the experiment.

Figure 3.

Examples of immunohistochemical detection of Oct-4 in sections of a lung hyperplastic and inflammatory nodule (A) and of an adenocarcinoma (B). See text for details. Original magnification 400×.