Effect of celecoxib and novel agent LC-1 in a hamster model of lung cancer.
BACKGROUND
Lung cancer is the leading cause of cancer deaths in the United States. Inflammatory molecules, cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-kappaB) have been implicated in lung carcinogenesis. The therapeutic potential of celecoxib, a COX-2 selective inhibitor, and LC-1, a pro-apoptotic drug with accompanying inhibition of NF-kappaB, were investigated.


METHODS
Syrian golden hamsters (n = 140) underwent N-nitroso-bis(2-oxopropyl)amine (BOP) injection weekly for 6 wk. Hamsters were randomized into seven groups: placebo and low/high doses of LC-1, celecoxib, and LC-1/celecoxib. Treatments were given via orogastric lavage for 32 wk. Immunohistochemistry was used to determine COX-2 expression and NF-kappaB activity. Ki-67 labeling was used as an index of proliferation. COX activity was measured by prostaglandin E(2) enzyme-linked immunosorbent assay.


RESULTS
BOP successfully induced lung adenocarcinoma in 63% of placebo animals. Lung tumors strongly expressed COX-2 and NF-kappaB. Prostaglandin E(2) levels were decreased in celecoxib compared with placebo groups (P < 0.05) reflecting suppression of COX activity, but no decrease in NF-kappaB 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 increased COX-2 and NF-kappaB expression and suggests a role in carcinogenesis. Celecoxib and LC-1 did not have any effect in preventing lung cancer development when co-administered with and continued after the carcinogen BOP. Higher doses that can result in suppression of NF-kappaB activity will need to be explored to determine the viability of this approach to prevent lung cancer development.
Vegeler
Reid C
RC
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Yip-Schneider
Michele T
MT
Ralstin
Matthew
M
Wu
Huangbing
H
Crooks
Peter A
PA
Neelakantan
Sundar
S
Nakshatri
Harikrishna
H
Sweeney
Christopher J
CJ
Schmidt
C Max
CM
D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002273:Carcinogens; D000068579:Celecoxib; D006224:Cricetinae; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008647:Mesocricetus; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009602:Nitrosamines; D011720:Pyrazoles / Q000627:therapeutic use*; D011897:Random Allocation; D012717:Sesquiterpenes / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use*
D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; C524858:LC-1 compound; D016328:NF-kappa B; D009602:Nitrosamines; D011720:Pyrazoles; D012717:Sesquiterpenes; D013449:Sulfonamides; C012457:diisopropanolnitrosamine; D051546:Cyclooxygenase 2; D000068579:Celecoxib