Abstract LB-182: Licofelone inhibits NNK-induced lung adenocarcinoma formation in A/J mice by suppressing COX/LOX and inhibits human lung cancer cell growth by p21 up-regulation.

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Abstract Lung cancer is the leading causes of cancer deaths. Inflammation plays an important role in lung tumor progression; in that eicosanoids levels derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) positively influence the tumor growth. We have evaluated chemopreventive effects of a novel dual LOX/ COX inhibitor, Licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice and its possible mode of action was evaluated using human lung cancer cell line A549. For bioassay, at 6 weeks of age, mice were randomized and fed control AIN-76A modified diet. At 7 weeks of age (25-mice/group) intended for carcinogen treatment received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after the NNK treatment, groups intended for Licofelone treatment were administered 200 and 400 ppm in diet for either 17 weeks (10 mice/group) and/or 34 weeks (15 mice/group) to assess efficacy against lung adenoma and adenocarcinoma. Intervention with 200 or 400 ppm Licofelone significantly suppressed lung adenomas by 29% (p<0.004) and 38.3% (p<0.0004); lung adenocarcinoma by 46% (p<0.0005) and 62% (p<0.0001), respectively after 17 weeks exposure. Also, dietary 200 and 400 ppm Licofelone significantly (p<0.0001) suppressed lung adenocarcinomas by 40% and 56%, respectively, after 34 weeks exposure. These results suggest that licofelone a dual 5LOX/COX inhibitor inhibits the NNK induced lung adenomas and more so by suppressing adenocarcinoma formation in a dose-dependent manner. IHC analysis of lung tumors from NNK treated mice exposed to licofelone showed a significantly reduced proliferating cell nuclear antigen (PCNA) positive index, increased TUNEL positive cells and p21 expression as compared to lung adenocarcinomas from NNK treated mice fed with control diet. Treatment with Licofelone significantly suppressed both COX and 5-LOX expression and its metabolite formation in NNK induced lung tumors and human lung cancer cell line growth inhibition was associated with p21-upregulation. These findings suggest that dietary Licofelone inhibits tobacco carcinogen-induced lung adenoma and adenocarcinoma formation in a dose-dependent manner by modulating COX-2 and 5-LOX activities. {Supported by NIH, NCI grants NO1-CN-53300 and Kerley-Cade Chair} Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Dhimant Desai, Shantu Amin, Stan Lightfoot, Chinthalapally V. Rao. Licofelone inhibits NNK-induced lung adenocarcinoma formation in A/J mice by suppressing COX/LOX and inhibits human lung cancer cell growth by p21 up-regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-182. doi:10.1158/1538-7445.AM2013-LB-182