title: R-Etodolac decreases beta-catenin levels along with survival and proliferation of hepatoma cells.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Behari
authors.forename: Gang
authors.initials: G
authors.lastname: Zeng
authors.forename: Wade
authors.initials: W
authors.lastname: Otruba
authors.forename: Michael D
authors.initials: MD
authors.lastname: Thompson
authors.forename: Peggy
authors.initials: P
authors.lastname: Muller
authors.forename: Amanda
authors.initials: A
authors.lastname: Micsenyi
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Sekhon
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Leoni
authors.forename: Satdarshan P S
authors.initials: SP
authors.lastname: Monga
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D017308:Etodolac / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D015820:Cadherins; D052246:Cyclooxygenase 2 Inhibitors; D006131:Growth Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D015534:Trans-Activators; D051176:beta Catenin; D017308:Etodolac; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000068579:Celecoxib