La Maestra Sebastiano, D'Agostini Francesco, Izzotti Alberto, Micale Rosanna T, Mastracci Luca, Camoirano Anna, Balansky Roumen, Trosko James E, Steele Vernon E, De Flora Silvio
Department of Surgical and Diagnostic Sciences, University of Genoa, 16132 Genoa, Italy.
National Center of Oncology, Sofia 1756, Bulgaria.
Carcinogenesis. 2015 Dec;36(12):1531-8. doi: 10.1093/carcin/bgv149. Epub 2015 Oct 13.
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.
化学预防为被动吸烟者的癌症控制提供了一项重要策略。由于烟雾相关的慢性炎症在肺癌发生过程中起着关键作用，因此广泛使用的药物制剂，如非甾体抗炎药（NSAIDs），备受关注。我们评估了环氧化酶 -1 和环氧化酶 -2 的抑制剂阿司匹林和萘普生调节环境香烟烟雾（ECS）诱导的两种性别的 A/J 小鼠肺癌发生的能力。基于对 180 只断奶后小鼠的亚慢性毒性研究，我们使用了 1600 mg/kg 饮食剂量的阿司匹林和 320 mg/kg 饮食剂量的萘普生。在肿瘤化学预防研究中，使用了 320 只小鼠，出生后不久开始暴露于 ECS，断奶后开始给予 NSAIDs。在 10 周龄时，NSAIDs 不影响粪便潜血的存在。在 40 只小鼠的亚组中评估发现，暴露于 ECS 的小鼠中大分子 DNA 加合物和 8 - 羟基 -2'-脱氧鸟苷水平显著增加，并且无论性别如何，两种 NSAIDs 均能显著抑制这些核苷酸改变。暴露 4 个月后再在过滤空气中饲养 5 个月，ECS 导致肺表面肿瘤发生率显著增加，其中 43.7% 为腺瘤，56.3% 为腺癌。在一些腺癌细胞中检测到细胞干性标志物 Oct-4（八聚体结合转录因子 4）。NSAIDs 降低了肺肿瘤的发生率，但仅在用阿司匹林治疗的雌性小鼠中，预防 ECS 诱导的肺腺瘤具有统计学意义，这支持了雌激素在 ECS 相关肺癌发生中的作用，并突出了 NSAIDs 的抗雌激素特性。
