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 β-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.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health grant P50 CA090440 and a grant to Dr. Stabile from the Lung Cancer Research Foundation. This project used the University of Pittsburgh Cancer Institute Animal Facility and University of Pittsburgh Cancer Institute Biostatistics Facility and was supported in part by award P30CA047904. This project also used the Masonic Cancer Center Animal Facility and was supported in part by award P30CA077598.
Disclosure: Dr. Diergaarde reports grants from the National Institutes of Health (NIH) during conduct of this study. Dr. Kurland reports grants from NIH during conduct of the study and personal fees from Celidex outside the submitted work. Dr. Siegfried reports grants from NIH during the conduct of this study. The remaining authors declare no conflict of interest.
© 2017 International Association for the Study of Lung Cancer
- Lung cancer