Sulindac Prevents Carcinogen-Induced Intrahepatic Cholangiocarcinoma Formation In Vivo

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

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4 Citations (Scopus)

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
JournalJournal of Surgical Research
Volume157
Issue number1
DOIs
StatePublished - Nov 2009

Fingerprint

Sulindac
Cholangiocarcinoma
Carcinogens
nitrosobis(2-oxopropyl)amine
Enzyme-Linked Immunosorbent Assay
Ethionine
Liver Extracts
Cyclooxygenase 1
Control Groups
NF-kappa B
Mesocricetus
Incidence
Non-Steroidal Anti-Inflammatory Agents
Cyclooxygenase 2
Choline
Cricetinae
Methionine
Western Blotting
Diet
Inflammation

Keywords

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

ASJC Scopus subject areas

  • Surgery

Cite this

@article{98608ea82cf34744a448ba6b1dbb9bb4,
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. 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.",
keywords = "chemoprevention, cholangiocarcinoma, cyclooxygenase, nuclear factor κ-B, sulindac",
author = "Wentz, {Sabrina C.} and Michele Yip-Schneider and Gage, {Earl A.} and Romil Saxena and Sunil Badve and C. Schmidt",
year = "2009",
month = "11",
doi = "10.1016/j.jss.2008.10.006",
language = "English",
volume = "157",
journal = "Journal of Surgical Research",
issn = "0022-4804",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Sulindac Prevents Carcinogen-Induced Intrahepatic Cholangiocarcinoma Formation In Vivo

AU - Wentz, Sabrina C.

AU - Yip-Schneider, Michele

AU - Gage, Earl A.

AU - Saxena, Romil

AU - Badve, Sunil

AU - Schmidt, C.

PY - 2009/11

Y1 - 2009/11

N2 - 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.

AB - 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.

KW - chemoprevention

KW - cholangiocarcinoma

KW - cyclooxygenase

KW - nuclear factor κ-B

KW - sulindac

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DO - 10.1016/j.jss.2008.10.006

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