Non-steroidal anti-inflammatory drugs inhibit cellular proliferation and upregulate cyclooxygenase-2 protein expression in endometrial cancer cells

Cancer Sci. 2004 Nov;95(11):901-7. doi: 10.1111/j.1349-7006.2004.tb02200.x.


We determined the effects of several non-steroidal anti-inflammatory drugs (NSAIDs), aspirin (acetylsalicylic acid, ASA), indomethacin and a cyclooxygenase-2 (COX-2)-selective inhibitor (NS398), on cellular proliferation and regulation of COX-2 protein expression in endometrial cancer cells in vitro, and investigated their modes of action. All three NSAIDs markedly inhibited the proliferation of Ishikawa, HEC-1A and AN3CA endometrial cancer cell lines in a time- and concentration-dependent manner. ASA and indomethacin triggered apoptosis in cells of all three lines through release of cytosolic cytochrome c, activation of caspase-9 and-3, and cleavage of poly(ADP-ribose) polymerase (PARP), but NS398 induced minimal apoptosis only in Ishikawa cells. ASA altered the cell cycle distribution, with G2/M phase accumulation of cells, and induced overexpression of Ki-67 protein. Both ASA and indomethacin reduced the protein levels of Bcl-2 and Bcl-xl, but upregulated those of Bax and Bcl-xs. COX-2 protein expression and PGE(2) production were upregulated by ASA and indomethacin in all three cell lines. However, NS398 did not alter COX-2 protein expression or PGE(2) production in these cells. These results indicate that NSAIDs inhibit proliferation of endometrial cancer cells independently of the reduction of COX-2 protein expression. A cytochrome c-dependent apoptotic pathway and/or cell cycle arrest may contribute to the inhibitory effects of these NSAIDs.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Apoptosis
  • Aspirin / pharmacology
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Endometrial Neoplasms / enzymology*
  • Enzyme Activation
  • Female
  • Humans
  • Indomethacin / pharmacology
  • Isoenzymes / metabolism*
  • Membrane Proteins
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Tumor Cells, Cultured


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Aspirin
  • Indomethacin