Effect of Celecoxib and Novel Agent LC-1 in a Hamster Model of Lung Cancer Reid C. Vegeler, B.A.,* Michele T. Yip-Schneider, Ph.D.,* ,  Matthew Ralstin, M.D.,* Huangbing Wu, B.S.,* Peter A. Crooks, Ph.D.,€ Sundar Neelakantan, Ph.D.,€ Harikrishna Nakshatri, Ph.D.,* , † , § ,  Christopher J. Sweeney, M.B.B.S.,‡ ,  and C. Max Schmidt, M.D., Ph.D.,* , † , § ,  ,¶,1 *Department of Surgery; †Department of Biochemistry/Molecular Biology; ‡Department of Hematology/Oncology; §Walther Oncology Center; Indiana University School of Medicine, Indianapolis, Indiana; Indiana University Cancer Center, Indianapolis, Indiana; ¶ Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; and €College of Pharmacy, University of Kentucky, Lexington, Kentucky Submitted for publication January 9, 2007 Background. Lung cancer is the leading cause of can- cer deaths in the United States. Inflammatory molecules, cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-B) have been implicated in lung carcinogenesis. The therapeutic potential of celecoxib, a COX-2 selective inhibitor, and LC-1, a pro-apoptotic drug with accompa- nying inhibition of NF-B, were investigated. Materials and methods. Syrian golden hamsters (n  140) underwent N-nitroso-bis(2-oxopropyl)amine (BOP) injection weekly for 6 wk. Hamsters were ran- domized into seven groups: placebo and low/high doses of LC-1, celecoxib, and LC-1/celecoxib. Treat- ments were given via orogastric lavage for 32 wk. Im- munohistochemistry was used to determine COX-2 ex- pression and NF-B activity. Ki-67 labeling was used as an index of proliferation. COX activity was mea- sured by prostaglandin E 2 enzyme-linked immunosor- bent assay. Results. BOP successfully induced lung adenocarci- noma in 63% of placebo animals. Lung tumors strongly expressed COX-2 and NF-B. Prostaglandin E 2 levels were decreased in celecoxib compared with placebo groups (P < 0.05) reflecting suppression of COX activ- ity, but no decrease in NF-B was seen as measured by immunohistochemistry in the tumors. There was no significant difference in tumor size, tumor incidence, or tumor proliferation index between placebo and treatment groups. Conclusions. Carcinogen exposure results in in- creased COX-2 and NF-B expression and suggests a role in carcinogenesis. Celecoxib and LC-1 did not have any effect in preventing lung cancer develop- ment when co-administered with and continued after the carcinogen BOP. Higher doses that can result in suppression of NF-B activity will need to be explored to determine the viability of this approach to prevent lung cancer development. © 2007 Elsevier Inc. All rights reserved. Key Words: celecoxib; cyclooxygenase (COX); lung cancer; nuclear factor kappa B (NF-B); parthenolide. INTRODUCTION Lung cancer is a common form of cancer and a lead- ing cause of cancer mortality worldwide [1]. Although third behind prostate and breast cancer in incidence, lung cancer is the leading cause of cancer mortality in the United States [2]. There are two main categories for lung cancer, small cell and non-small cell lung cancer (NSCLC). Non-small cell lung cancer accounts for approximately 80% of lung cancers with the domi- nant sub-group being adenocarcinoma [3]. Five-year survival rates for lung cancer in the U.S. remain close to 15%, the highest for any country in the world [1]. The majority of available therapies for lung cancer, however, are ineffective. Several treatment op- tions, including surgery, radiation, chemotherapy, and combined therapies offer only marginal benefits. Nota- bly, the chemotherapeutic options for NSCLC result in a modest increase in overall survival but are not cur- ative [4, 5]. Novel therapeutic agents and strategies are clearly needed. Based upon a strong connection between inflammation and lung cancer [6 –9], two promising molecular treatment targets have been iden- tified, cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-B) [10 –12]. 1 To whom correspondence and reprint requests should be addressed at Department of Surgery, Indiana University School of Medicine, 1044 W. Walnut St., Building R4, Rm. 041, Indianapolis, IN 46202, USA. E-mail: maxschmi@iupui.edu or myipschn@iupui.edu. Journal of Surgical Research 143, 169 –176 (2007) doi:10.1016/j.jss.2007.08.007 169 0022-4804/07 $32.00 © 2007 Elsevier Inc. All rights reserved.