title: Sulindac prevents carcinogen-induced intrahepatic cholangiocarcinoma formation in vivo.
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.
  
  
  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).
  
  
  CONCLUSIONS
  Sulindac effectively prevents experimental cholangiocarcinogenesis, in part by inhibiting the NF-kappaB pathway.
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, USA.
authors: Sabrina C
authors: SC
authors: Wentz
authors: Michele T
authors: MT
authors: Yip-Schneider
authors: Earl A
authors: EA
authors: Gage
authors: Romil
authors: R
authors: Saxena
authors: Sunil
authors: S
authors: Badve
authors: C Max
authors: CM
authors: Schmidt
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D001652:Bile Ducts / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D006224:Cricetinae; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008647:Mesocricetus; D000072000:NF-KappaB Inhibitor alpha; D009602:Nitrosamines / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002273:Carcinogens; D020672:I-kappa B Proteins; D009602:Nitrosamines; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D013467:Sulindac; C013622:nitrosobis(2-oxopropyl)amine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone