Therapeutic effect of CS-706, a specific cyclooxygenase-2 inhibitor, on gallbladder carcinoma in BK5.ErbB-2 mice

Abstract

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 f90% 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.

Regulation of inflammation in cancer by eicosanoids

“…We and others have demonstrated the anti-tumor activity of COX-2 inhibitors in inflammation-associated experimental tumor models including transplantable and genetically engineered models of cancer (36, 43, 102-104). COX-2 inhibitors initially did not exhibit the toxicity associated with aspirin, such as gastrointestinal bleeding.…”

High-resolution transrectal ultrasound: Pilot study of a novel technique for imaging clinically localized prostate cancer

“…Although these low frequencies allow for adequate imaging of the prostate in contrast to adjacent structures, they are suboptimal in delineating intraprostatic architecture. High-resolution (16-21 MHz) ultrasound probes have been available for cutaneous and small animal imaging for some time [13,14], but a high-resolution TRUS (HiTRUS) probe for prostatic imaging was developed only recently. This higher resolution equipment may represent a needed advance in prostate cancer visualization at the clinically localized stage, particularly in the peripheral zone.…”

Molecular aspects of cholangiocarcinoma

“…CS‐706 treatment also downregulated the activation of ErbB‐2 and EGFR, resulting in decreased levels of phosphorylated Akt and COX‐2 in GBCs of BK5.erbB2 mice (Fig. ) .…”

“…Figures are adopted from Kiguchi et al. 2007 Right panel. Western blot analysis of ErbB‐2, p‐ErbB‐2, EGFR, p‐EGFR, Akt, and phosphorylated Akt (p‐Akt) levels in the gallbladders of BK5.erbB‐2 mice on control diet and BK5.erbB‐2 mice treated with 100 ppm CS‐706 Epithelial cell lysates were prepared from gallbladder tumors from five BK5.erbB‐2 mice, and gallbladders from BK5.erbB‐2 mice treated with CS‐706 were pooled.…”