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. MATERIALS AND 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.
RCT Entities:
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. MATERIALS AND 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.
Authors: Narsimha Reddy Penthala; Venumadhav Janganati; Terri L Alpe; Scott M Apana; Marc S Berridge; Peter A Crooks; Michael J Borrelli Journal: Bioorg Med Chem Lett Date: 2016-11-09 Impact factor: 2.823