R-Etodolac decreases beta-catenin levels along with survival and proliferation of hepatoma cells

J Hepatol. 2007 May;46(5):849-57. doi: 10.1016/j.jhep.2006.11.017. Epub 2006 Dec 21.

Abstract

Background/aims: Inhibition of hepatoma cells by cyclooxygenase (COX)-2-dependent and -independent mechanisms has been shown previously. Here, we examine the effect of Celecoxib, a COX-2-inhibitor and R-Etodolac, an enantiomer of the nonsteroidal anti-inflammatory drug Etodolac, which lacks COX-inhibitory activity, on the Wnt/beta-catenin pathway and human hepatoma cells.

Methods: Hep3B and HepG2 cell lines were treated with Celecoxib or R-Etodolac, and examined for viability, DNA synthesis, Wnt/beta-catenin pathway components, and downstream target gene expression.

Results: Celecoxib at high doses affected beta-catenin protein by inducing its degradation via GSK3beta and APC along with diminished tumor cell proliferation and survival. R-Etodolac at physiological doses caused decrease in total and activated beta-catenin protein secondary to decrease in its gene expression and post-translationally through GSK3beta activation. In addition, increased beta-catenin-E-cadherin was also observed at the membrane. An associated inhibition of beta-catenin-dependent Tcf reporter activity, decreased levels of downstream target gene products glutamine synthetase and cyclin-D1, and decreased proliferation and survival of hepatoma cells was evident.

Conclusions: The antitumor effects of Celecoxib (at high concentrations) and R-Etodolac (at physiological doses) on HCC cells were accompanied by the down-regulation of beta-catenin demonstrating a useful therapeutic strategy in hepatocellular cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Cadherins
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Celecoxib
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Etodolac / chemistry
  • Etodolac / pharmacology*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Growth Inhibitors / pharmacology
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Pyrazoles / pharmacology*
  • Sulfonamides / pharmacology*
  • Trans-Activators*
  • Tumor Cells, Cultured
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / drug effects
  • beta Catenin / metabolism*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • Cadherins
  • Cyclooxygenase 2 Inhibitors
  • Growth Inhibitors
  • Pyrazoles
  • Sulfonamides
  • Trans-Activators
  • beta Catenin
  • Etodolac
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • Celecoxib