Abstract 2135: Chemoprevention of tobacco carcinogen-induced lung cancer by DFMO and Licofelone administered individually or in combination in female A/J mice

Abstract

Abstract Lung cancer is the leading cause of cancer death among both men and women in the US. Inflammatory eicosanoids and leukotrienes derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) pathway positively influences lung tumor growth. Overexpression of ornithine decarboxylase (ODC) enzyme activity and polyamines has been associated with proliferation and progression of lung cancer. Thus, targeting both tumor inflammatory molecules and polyamines synthesis may provide additive/synergistic antitumor effects. To overcome clinical toxicity of high dose difluoromethyl ornithine (DFMO), an inhibitor of ODC; and to target both COX-2/5LOX, we tested low dose DFMO combined with Licofelone, a novel dual inhibitor COX-2/5-LOX, in lung cancer model. At 7 weeks of age, mice (25 mice/group) were treated with 10 μmol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) /mouse to induce the lung tumors. Three weeks after the NNK treatment, mice were fed either control or experimental diets containing 200, 400 ppm licofelone or 1500 and 3000 ppm DFMO or low-dose combinations of both agents. Mice were killed at 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) after NNK-treatment for lung tumor evaluation. Administration of 200 and 400 ppm licofelone significantly suppressed lung tumor (adenoma + adenocarcinoma) formation by >32 to 35% (p43 to 47% (p25 to 30% (p44% (p53% (p60% (p<0.0001) respectively at 17 and 34 weeks exposure. These results suggest that low-dose combinations of licofelone and DFMO inhibit the NNK-induced lung adenocarcinoma formation synergistic/additive manner. Immunohistochemistry analysis revealed that lung tumors from mice exposed to licofelone plus DFMO showed significantly reduced proliferating cell nuclear antigen (PCNA)-positive index, increased accumulation of TUNEL positive cells as compared to lung tumors from NNK-treated mice fed with control diet. These results demonstrate the targeting lung tumor COX-LOX with ODC may provide better efficacy when compared to individual targets on tobacco carcinogen-induced lung adenocarcinomas formation. {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, Michael K. Sadeghi, Dhimant Desai, Shantu Amin, Stan Lightfoot, Vernon E. Steele, Chinthalapally V. Rao. Chemoprevention of tobacco carcinogen-induced lung cancer by DFMO and Licofelone administered individually or in combination in female A/J mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2135. doi:10.1158/1538-7445.AM2014-2135