Preclinical Evidence for Combined Use of Aromatase Inhibitors and NSAIDs as Preventive Agents of Tobacco-Induced Lung Cancer.

A hormonal role in non-small cell lung cancer (NSCLC) development is well documented. We previously showed that the aromatase inhibitor (AI) anastrozole decreased the development of tobacco carcinogen-induced lung tumors in a murine lung cancer prevention model and that aromatase and estrogen receptor (ER) were expressed in pulmonary inflammatory cells.We utilized a tobacco carcinogen-induced lung tumor mouse model [4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)] to determine whether an AI combined with non-steroidal anti-inflammatory drugs (NSAIDs) results in greater lung tumor prevention effects than single agent treatment.Combination of anastrozole (0.1mg/kg/day) with aspirin (25mg/kg/day) following NNK exposure resulted in significantly fewer and smaller lung tumors compared to single agent treatments, accompanied by maximum decreases in circulating β-estradiol (E2) and IL-6, tumor infiltrating macrophages and tumoral Ki67, P-MAPK, P-STAT3 and IL-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 anti-tumor effects. Moreover, male mice treated with NNK that received E2 in the drinking water showed greater levels of pulmonary macrophages and inflammatory markers compared to control, confirming an E2 effect on inflammation in the microenvironment.Our results suggest a benefit to joint targeting of the estrogen and inflammatory pathways for NSCLC prevention. Combining AIs with NSAIDs reduces circulating E2, pro-inflammatory cytokines, and macrophage recruitment in the lung microenvironment following tobacco exposure. This strategy could be particularly effective in women who have underlying pulmonary inflammatory diseases.