Celecoxib leads to G2/M arrest by induction of p21 and down-regulation of cyclin B1 expression in a p53-independent manner

Eur J Cancer. 2006 Feb;42(3):422-6. doi: 10.1016/j.ejca.2005.11.009. Epub 2006 Jan 19.

Abstract

A unique in vitro system has been developed in our lab that consists of normal enterocytes derived from the rat ileum (IEC-18 cells) and their transformed derivatives with c-K-ras (R1 cells), anti-sense bak (B3 cells) and cyclin D1 (D1 cells). R1 and B3 cells express high level of COX-2 protein and PGE2. IEC 18 and D1 cells express negligible amount of COX-2, and produce very low level of PGE2. A relatively low dose of celecoxib (5-10 microM) induced G2/M arrest, followed by induction of apoptosis in the transformed but not in the normal cells. Down-regulation of cyclin B1 and up-regulation of p21 expressions independent of p53 might have cause this cell cycle block. Growth inhibition was related to COX-2 function with 90-95% reduction in PGE2 production. These findings may be of clinical importance, since low concentration of celecoxib can be achieved in human serum following standard anti-inflammatory (100-200 mg bid) regime.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Celecoxib
  • Colorectal Neoplasms / drug therapy*
  • Cyclin B / drug effects*
  • Cyclin B / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / drug effects
  • Cyclooxygenase 2 / drug effects
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Dinoprostone / metabolism
  • Down-Regulation / drug effects
  • Enterocytes / drug effects
  • Flow Cytometry
  • G2 Phase / drug effects*
  • Genes, ras / drug effects
  • Humans
  • Pyrazoles / pharmacology*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology*
  • Tumor Suppressor Protein p53 / drug effects

Substances

  • Cdkn1a protein, mouse
  • Cyclin B
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclooxygenase 2 Inhibitors
  • Pyrazoles
  • Sulfonamides
  • Tumor Suppressor Protein p53
  • Cyclooxygenase 2
  • Celecoxib
  • Dinoprostone