Abstract LB-176: Chemoprevention of NNK-induced lung adenoma and adenocarcinoma in A/J mice by p53 modulating agents, CP-31398 and Prima-1

Abstract

Abstract Lung cancer is a leading cause of cancer deaths worldwide. p53 Mutations including wild-type p53 nuclear localization due to excessive endogenous electrophilic molecules are highly prevalent in tobacco associated lung cancers. Here, we report the chemopreventive effects of direct-acting p53 modulating agents, CP-31398 and Prima-1 on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma in female A/J mice. Seven weeks-old mice on a regular AIN-76A diet, received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after NNK treatment, groups of mice (25 mice/group) were fed control AIN-76A or experimental diets containing 50 and 100 ppm CP-31398, or 150 and 300 ppm Prima-1. Mice were sacrificed after 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) following NNK-treatment and evaluated for lung adenomas and adenocarcinomas by histopathological methods. Administration of 50 and 100 ppm CP-31398 significantly suppressed lung tumor formation by 29% and 39.5% (P<0.01-0.0001), respectively after 20 weeks and 32.2% and 40.1% (P<0.01-0.0001), respectively after 36 weeks. Similarly, 150 and 300 ppm Prima-1 significantly suppressed lung tumor formation by 22.2% and 34% (P<0.04-0.0001) after 20 weeks and 28.8% and 47.4% (P<0.01-0.0001) after 36 weeks, respectively. Inhibition of NNK-induced lung adenocarcinoma by either agent was greater than 55-72% (p<0.0001) after 20 weeks and about 40-57% after 36 weeks. These results suggest that restoring/activating wild-type p53 function by small molecules significantly inhibits NNK-induced lung tumor in A/J mice, most notably delaying progression of adenomas to adenocarcinoma. IHC analysis of lung tumors from NNK-treated mice exposed to either CP-31398 or Prima-1 showed a significantly reduced proliferating cell nuclear antigen (PCNA)-positive index, increased accumulation of nuclear wt-p53 including increased p21 and TUNNEL positive cells compared to lung tumors from NNK-treated mice fed with control diet. Incidentally, neither COX-1 nor iNOS were significantly affected by CP-31398 or Prima -1 in the NNK derived lung tumors. These results demonstrate, for the first time, the chemopreventive role of p53 modulating agents on tobacco specific carcinogen-induced lung adenocarcinomas. {Supported by NIH, NCI grants NO1-CN-53300}. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-176. doi:1538-7445.AM2012-LB-176