Nicotine Does Not Promote Tumor Growth In Preclinical Mouse Models Of Lung Cancer

Nicotine replacement therapy (NRT) is a popular and effective regimen for the cessation of smoking. Expanded use of NRT is controversial based on preclinical studies that show that nicotine activates signaling pathways that promote cellular survival and proliferation. To address the tumor promoting effects of nicotine in mouse models of lung cancer, nicotine was administered in the drinking water and tested in a tobacco carcinogen-driven model (NNK), a genetically engineered model (KRasLA2), and syngeneic mouse xenografts. Pharmacokinetic analysis showed that mice had normal water consumption and achieved an average serum cotinine level of 135 ng/ml, a level comparable to that observed in NRT users. In the NNK model, nicotine was administered after 3 weekly intraperitoneal injections of NNK, and was continued for 12 wk. At the time of sacrifice, nicotine did not increase lung tumor multiplicity or size, and did not activate the Akt/mTOR pathway. In the KRasLA2 model, mice were placed on nicotine at the time of weaning. At 6 wk, there was no effect on tumor multiplicity, size, histology, or tumor biomarkers. Studies assessing the effects of nicotine on overall survival of K-RasLA2 mice are ongoing. Similar negative results were observed with nicotine administration in xenograft studies with isogenic NNK-transformed lung adenocarcinoma cell lines. To assess whether the response to nicotine might be dose-dependent, we assessed activation of the PI3K/Akt/mTOR, MEK/ERK, and JAK/STAT pathways in these cell lines using immunoblotting. Stimulation was only observed at concentrations higher than that observed with NRT. These results suggest nicotine at doses comparable to NRT does not promote lung tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1336. doi:10.1158/1538-7445.AM2011-1336