Sulindac Prevents Carcinogen-Induced Intrahepatic Cholangiocarcinoma Formation In Vivo

Wentz, Sabrina C.; Yip-Schneider, Michele T.; Gage, Earl A.; Saxena, Romil; Badve, Sunil; Schmidt, C. Max

doi:10.1016/j.jss.2008.10.006

« Previous Next »Journal of Surgical Research
Volume 157, Issue 1 , Pages e87-e95, November 2009

Sulindac Prevents Carcinogen-Induced Intrahepatic Cholangiocarcinoma Formation In Vivo

Sabrina C. Wentz, M.D.
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
Michele T. Yip-Schneider, Ph.D.
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
- Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana
Earl A. Gage, M.D.
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
Romil Saxena, M.D.
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
Sunil Badve, M.D.
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
C. Max Schmidt, M.D., Ph.D.
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
- Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana
- Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
- Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana
- Richard L. Roudebush VAMC, Indiana University School of Medicine, Indianapolis, Indiana
- To whom correspondence and reprint requests should be addressed at Departments of Surgery and Biochemistry, Cancer Research Institute, Molecular Biology, 1044 W Walnut St. R4-039, Indianapolis, IN 46202.

Received 30 June 2008 published online 10 November 2008.

Background

Intrahepatic cholangiocarcinoma (ICC) incidence and mortality are increasing in the United States and worldwide. ICC etiologies involve chronic inflammation. We hypothesize that the nonsteroidal anti-inflammatory agent sulindac may prevent ICC by targeting cyclooxygenase-1 and -2 (COX-1, -2) as well as COX-independent pathways.

Materials and Methods

ICC was induced with the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) in Syrian golden hamsters. Cholangiocarcinogenesis was accelerated by a choline-deficient diet and administration of DL-ethionine and L-methionine. Hamsters were gavaged twice daily for 10 wk with vehicle or sulindac 25, 50, or 75 mg/kg/dose. Harvested livers underwent gross and histopathological examinations. Tissues were analyzed by immunostaining, Western blot, and enzyme-linked immunosorbent assay (ELISA).

Results

ICC incidence and multiplicity were decreased in sulindac treatment groups versus control (P < 0.05). In addition, ICC and nontumor lesion sizes decreased in treatment versus control animals. Proliferative indices (Ki-67 immunostaining) decreased and apoptosis (ApopTag immunostaining) increased in treatment versus control (P < 0.05). No changes in COX-1 and -2 protein levels were detected by Western blot. Furthermore, prostaglandin E₂ (PGE₂) levels were unchanged in treatment and control serum and liver tissues (P > 0.05), suggesting that the antitumor effects of sulindac are mediated by COX-independent mechanisms. Nuclear p65 (activated NF-κB) immunostaining decreased (P < 0.05), and protein levels of the NF-kB inhibitor IκB-α increased in treatment versus control groups. p65 ELISA of liver extracts confirmed decreased NF-κB binding activity in sulindac-treated versus control animals (P < 0.05).