Biliary tract cancer is still challenging to treat and manage due to its poor sensitivity to conventional
therapies and the inability to prevent or detect the early
tumor formation. The most well known risk factor for
gallbladder cancer is the presence of chronic
inflammation, usually related to
gallstones. It has been suggested that
cyclooxygenase-2 (COX-2) plays a variety of roles in the gastrointestinal tract, including pathogenic processes such as
neoplasia. Recently, we have generated transgenic mice that overexpress rat ErbB-2 under the control of bovine
keratin 5 promoter (BK5.ErbB-2 mice). Homozygous BK5.ErbB-2 mice develop
adenocarcinoma of gallbladder with an approximately 90% incidence. In addition to the activation of ErbB-2 and
epidermal growth factor receptor,
mRNA and
protein levels of COX-2 were up-regulated in the gallbladder
carcinomas that developed in these transgenic mice. The aim of this study was to examine the effects of a
COX-2 inhibitor,
CS-706, on the development of gallbladder
carcinomas using the BK5.ErbB-2 mouse model. Ultrasound image analysis as well as histologic evaluation revealed a significant
therapeutic effect of
CS-706 on the gallbladder
tumors, either as reversion to a milder phenotype or inhibition of
tumor progression. The antitumor effect was associated with inhibition of
prostaglandin E(2) synthesis.
CS-706 treatment also down-regulated the activation of ErbB-2 and
epidermal growth factor receptor, resulting in decreased levels of phosphorylated Akt and COX-2 in
gallbladder cancers of BK5.ErbB-2 mice. Based on our results, targeting COX-2 could provide a potentially new and effective
therapy alone or in combination with other therapeutic agents for patients with
biliary tract cancer.