Sulindac prevents carcinogen-induced intrahepatic cholangiocarcinoma formation in vivo

J Surg Res. 2009 Nov;157(1):e87-95. doi: 10.1016/j.jss.2008.10.006. Epub 2008 Nov 7.

Abstract

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 E(2) (PGE(2)) 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-kappaB) immunostaining decreased (P < 0.05), and protein levels of the NF-kB inhibitor IkappaB-alpha increased in treatment versus control groups. p65 ELISA of liver extracts confirmed decreased NF-kappaB binding activity in sulindac-treated versus control animals (P < 0.05).

Conclusion: Sulindac effectively prevents experimental cholangiocarcinogenesis, in part by inhibiting the NF-kappaB pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Bile Duct Neoplasms / chemically induced
  • Bile Duct Neoplasms / pathology
  • Bile Duct Neoplasms / prevention & control*
  • Bile Ducts / pathology
  • Bile Ducts, Intrahepatic* / pathology
  • Carcinogens / pharmacology
  • Cell Division / drug effects
  • Cholangiocarcinoma / chemically induced
  • Cholangiocarcinoma / pathology
  • Cholangiocarcinoma / prevention & control*
  • Cricetinae
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism
  • Female
  • I-kappa B Proteins / antagonists & inhibitors
  • I-kappa B Proteins / metabolism
  • Mesocricetus
  • NF-KappaB Inhibitor alpha
  • Nitrosamines / pharmacology
  • Sulindac / pharmacology*
  • Transcription Factor RelA / antagonists & inhibitors
  • Transcription Factor RelA / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • Carcinogens
  • I-kappa B Proteins
  • Nitrosamines
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Sulindac
  • nitrosobis(2-oxopropyl)amine
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Dinoprostone