Sulindac Prevents Carcinogen-Induced Intrahepatic Cholangiocarcinoma Formation In Vivo

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

Original languageEnglish (US)
Pages (from-to)e87-e95
JournalJournal of Surgical Research
Volume157
Issue number1
DOIs
StatePublished - Nov 1 2009

Keywords

  • chemoprevention
  • cholangiocarcinoma
  • cyclooxygenase
  • nuclear factor κ-B
  • sulindac

ASJC Scopus subject areas

  • Surgery

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