Celecoxib inhibits growth of tumors in a syngeneic rat liver metastases model for colorectal cancer

Abstract

Introduction Nonsteroidal anti-inXammatory drugs (NSAIDs) have been shown to reduce the risk of colorectal cancer in cyclooxygenase-2 (COX-2) overexpressing colorectal cancers. The present study was designed to evaluate the inhibitory eVects of the COX-2 inhibitor celecoxib on the growth of colorectal cancer liver metastases in a syngeneic rat model, CC531. Materials and methods The eVects of celecoxib on cell viability in vitro were evaluated by treatment of CC531 tumor cell cultures with celecoxib. In vivo, Wag/Rij rats were inoculated with CC531 tumor cells at two sites in the liver and treated with celecoxib starting one week before, or directly after tumor inoculation. Control rats were inoculated without treatment. Three weeks after tumor inoculation rats were sacriWced. Tumor size, immune cell inWltration, caspase-3 activity, PGE 2 and celecoxib levels were determined.Results CC531 tumors did not show COX-2 expression. Tumor growth was signiWcantly inhibited by celecoxib treatment in a dose dependent manner. Immune cell inWltration was decreased after celecoxib treatment, indicating that the immune system was not involved in preventing tumor growth. Tumor caspase-3 levels were only signiWcantly increased if treatment was started before tumor inoculation. Celecoxib serum concentration starting at 0.84 g/ml signiWcantly inhibited the outgrowth of CC531 liver tumors. In contrast, in vitro concentrations of celecoxib of at least 12 g/ml were needed to aVect tumor cell viability. Conclusion These results suggest that the inhibitory eVects of celecoxib on tumor growth are not by direct cytotoxicity, but by creating an unfavorable environment for tumor growth.

Gene expression profiling of liver metastases from colorectal cancer as potential basis for treatment choice

“…COX-2 overexpression may suggest a more aggressive phenotype of this kind of metastases that require a treatment preferentially directed against tumour angiogenesis, such as bevacizumab-based combinations or a treatment creating an unfavourable environment for tumour growth as recently published with COX-2 inhibitors (de Heer et al, 2008).…”

Anti-inflammatory, anti-proliferative and antioxidant profiles of selective cyclooxygenase-2 inhibition as chemoprevention for rat bladder carcinogenesis

“…20 Furthermore, a key role for COX-2 in carcinogenesis has been given by the positive effect of its downregulation on tumors incidence both in clinical and experimental studies for distinct types of tumors, including the bladder cancer. 17,18,[21][22][23]26 A chemopreventive role for COX-2 inhibition in bladder cancer was previously reported in animal models, [26][27][28] but the mechanisms by which these compounds are able to act on carcinogenesis remain to be elucidated. In our study, the COX-2 inhibitor (CEL) has promoted a remarkable chemopreventive effect on bladder cancer development.…”

“…20 According to several studies, the modulation of mice COX-2 levels and/or activity, by genetic deletion or chemical inhibition, has decreased tumors development. Therefore, the use of selective COX-2 inhibitors (Coxibs) for chemoprevention was already tested in other types of cancer, [21][22][23] but its efficacy in bladder cancer has been poorly investigated.…”

Potent Antitumor Activity in Experimental Hepatocellular Carcinoma by Adenovirus-Mediated Coexpression of TRAIL and shRNA against COX-2

“…In contrast to fetal hepatocytes, which expressed COX-2 in response to proinflammatory stimuli, adult hepatocytes failed to express COX-2 regardless of the type of challenge (19). However, overexpression of COX-2 was commonly related to different types of carcinomas, including hepatocellular carcinoma (20)(21)(22)(23). It was evident that COX-2 could enhance hepatocellular carcinoma invasiveness by promoting hepatocellular carcinoma proliferation and tumor angiogenesis (24,25).…”

“…Therefore, inhibition of COX-2 could exhibit therapeutic potential to hepatocellular carcinoma. It has been shown that COX-2-selective nonsteroidal anti-inflammatory drugs (NSAID) could induce apoptosis and inhibition of angiogenesis in hepatocellular carcinoma (17,22,26,27). COX-2 inhibition triggered expression of CD95, tumor necrosis factor (TNF)-R, and TRAIL-R1 and TRAIL-R2 death receptors.…”