Introduction: A hormonal role in NSCLC development is well documented. We previously showed that the aromatase inhibitor (AI) anastrozole decreased development of tobacco carcinogen‐induced lung tumors in a murine lung cancer prevention model and that aromatase and estrogen receptor were expressed in pulmonary inflammatory cells. Methods: We utilized a tobacco carcinogen–induced lung tumor mouse model by treatment with 4‐(methylnitrosoamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK), to determine whether an AI combined with nonsteroidal anti‐inflammatory drugs results in greater lung tumor prevention effects compared to single‐agent treatment. Results: Combination of anastrozole (0.1 mg/kg/d) with aspirin (25 mg/kg/d) after NNK exposure resulted in significantly fewer and smaller lung tumors than did single‐agent treatments and was accompanied by maximum decreases in circulating &bgr;‐estradiol (E2) and interleukin‐6, tumor‐infiltrating macrophages, and tumoral Ki67, phospho–mitogen‐activated protein kinase, phospho–signal transducer and activator of transcription 3, and interleukin‐17A expression. Preneoplasia arising after combination treatment showed the lowest Sox‐2 expression, suggesting an inhibitory effect on proliferative capacity in the airways by blocking both E2 and inflammation. Anastrozole combined with ibuprofen instead of aspirin also showed enhanced antitumor effects. Moreover, male mice treated with NNK that received E2 in their drinking water showed greater levels of pulmonary macrophages and inflammatory markers than did the control, confirming an E2 effect on inflammation in the microenvironment. Conclusions: Our results suggest a benefit to joint targeting of the estrogen and inflammatory pathways for NSCLC prevention. Combining AIs with nonsteroidal anti‐inflammatory drugs reduces circulating E2, proinflammatory cytokines, and macrophage recruitment in the lung microenvironment after tobacco exposure. This strategy could be particularly effective in women who have underlying pulmonary inflammatory diseases.

中文翻译：

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联合使用芳香酶抑制剂和 NSAIDs 作为烟草诱发的肺癌预防剂的临床前证据

简介：激素在 NSCLC 发展中的作用已得到充分证明。我们之前的研究表明，芳香酶抑制剂 (AI) 阿那曲唑可减少小鼠肺癌预防模型中烟草致癌物诱导的肺部肿瘤的发展，并且芳香酶和雌激素受体在肺部炎症细胞中表达。方法：我们利用 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 治疗烟草致癌物诱导的肺肿瘤小鼠模型，以确定 AI 联合非甾体抗炎药是否会导致与单药治疗相比，肺肿瘤预防效果更好。结果：阿那曲唑（0. 1 mg/kg/d) 和阿司匹林 (25 mg/kg/d) 在 NNK 暴露后导致肺肿瘤比单药治疗显着更少和更小，并且伴随循环 β-雌二醇 (E2) 和白细胞介素-6、肿瘤浸润巨噬细胞和肿瘤性 Ki67、磷酸-丝裂原活化蛋白激酶、磷酸-信号转导和转录激活因子 3，以及白介素-17A 表达。联合治疗后出现的肿瘤前期表现出最低的 Sox-2 表达，表明通过阻断 E2 和炎症对气道增殖能力有抑制作用。阿那曲唑联合布洛芬代替阿司匹林也显示出增强的抗肿瘤作用。而且，在饮用水中接受 E2 的 NNK 治疗的雄性小鼠表现出比对照组更高水平的肺巨噬细胞和炎症标志物，证实了 E2 对微环境中炎症的影响。结论：我们的结果表明联合靶向雌激素和炎症通路对 NSCLC 预防有益。将 AI 与非甾体抗炎药结合使用可减少烟草暴露后肺微环境中的循环 E2、促炎细胞因子和巨噬细胞募集。这种策略可能对患有潜在肺部炎症疾病的女性特别有效。我们的结果表明联合靶向雌激素和炎症通路有利于 NSCLC 预防。将 AI 与非甾体抗炎药结合使用可减少烟草暴露后肺微环境中的循环 E2、促炎细胞因子和巨噬细胞募集。这种策略可能对患有潜在肺部炎症疾病的女性特别有效。我们的结果表明联合靶向雌激素和炎症通路有利于 NSCLC 预防。将 AI 与非甾体抗炎药结合使用可减少烟草暴露后肺微环境中的循环 E2、促炎细胞因子和巨噬细胞募集。这种策略可能对患有潜在肺部炎症疾病的女性特别有效。