Abstract B111: Early and Delayed Rapamycin prevents NNK-induced lung adenocarcinoma in A/J mice

Abstract

Abstract Lung cancer is the leading cause of cancer deaths. Several studies have shown that nicotine and its metabolite, the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), activate the Akt/mTOR pathway, which maintains lung tumor cell proliferation and survival. Targeting this pathway might be one of the options for lung cancer chemoprevention. We studied chemopreventive effects of Rapamycin by intervening at two different stages of NNK-induced lung adenoma and adenocarcinoma formation in female A/J mice. At 6 weeks of age, groups of mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age, 40 mice from each group intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups of mice (25/group) were fed either control or experimental diets containing 8 or 16 ppm Rapamycin as an early stage intervention. Mice were continued on the respective diets and killed at 20 weeks (10 mice/group) after NNK-treatment and tumors were evaluated by histopathological methods. At 20 weeks - after tumors were allowed to form, another two groups (15 mice/group) were administered experimental diets containing 8 or 16 ppm Rapamycin as a late stage intervention and continued on the respective diets. Mice were killed at 36 weeks (15 mice/group) after both early stage and late stage interventions. Administration of 8 or 16 ppm Rapamycin as an early or a late stage intervention significantly suppressed lung adenoma and adenocarcinoma formation (p<0.01-0.0001) at 20 weeks and at 36 weeks. Rapamycin caused suppression of NNK-induced lung adenocarcinoma at both stages, but the effect was more pronounced at the early stage intervention >50-60% (P< 0.0001). Rapamycin treatment decreased the size of NNK-induced tumors from >2.10 to <∼0.75 mm3 (p=0.0056). Lung tumors harvested from mice exposed to Rapamycin showed a significant decrease in phosphorylation of S6 kinase (p-S6K) and phospho-Akt (p-Akt) when compared to control in both the early and the late stage intervention studies. Immunohistochmical analysis revealed that lung tumors from Rapamycin-treated mice had significantly reduced proliferating cell nuclear antigen (P<0.05) and p-S6 (P<0.005)-positive cells. These observations support the benefit of targeting the Akt/mTOR pathways in development of early interventions for lung cancer chemoprevention. {Supported by NIH, NCI grants NO1-CN-53300} Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Dhimant Desai, Shantu Amin, Stan Lightfoot, Chinthalapally V. Rao. Early and delayed rapamycin prevents NNK-induced lung adenocarcinoma in A/J mice. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B111.