Inhibition of cyclooxygenase-2 and activation of peroxisome proliferator-activated receptor-gamma synergistically induces apoptosis and inhibits growth of human breast cancer cells

Int J Mol Med. 2003 Jun;11(6):733-6.

Abstract

Cyclooxygenase-2 (COX-2) expression and peroxisome proliferator-activated receptor-gamma (PPARgamma) inactivation are linked to increased risk of human breast cancer. This study examines the effect of simultaneous targeting of COX-2 and PPARgamma on the proliferation of human breast cancer cells and on the expression of Bcl-2, BAX, and caspases-3 and -9, modulators of apoptotic cell death. Treatment of MDA-MB-231 breast cancer cells with NS-398 (a COX-2 inhibitor) or ciglitazone (CGZ, a PPARgamma-ligand) significantly inhibited cell proliferation and markedly increased apoptotic rates. These effects were accompanied by upregulation of BAX and caspases-3 and -9 mRNA expression and downregulation of Bcl-2. Compared to the influence of separate treatments, simultaneous treatment with NS-398 and CGZ synergistically inhibited cell proliferation and induced apoptotic cell death. In conclusion, combinational targeting of COX-2 and PPARgamma can inhibit the growth of human breast cancer cells and induce apoptosis to an extent more suprior to that produced by targeting each molecule alone. COX-2 and PPARgamma can be promising molecular targets for combinational chemoprevention or treatment of breast cancer.

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Caspase 3
  • Caspases / genetics
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Female
  • Gene Expression / drug effects
  • Genes, bcl-2
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Membrane Proteins
  • Nitrobenzenes / pharmacology
  • Prostaglandin-Endoperoxide Synthases
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Sulfonamides / pharmacology
  • Thiazolidinediones / pharmacology
  • Transcription Factors / metabolism*
  • bcl-2-Associated X Protein

Substances

  • BAX protein, human
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Nitrobenzenes
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptors, Cytoplasmic and Nuclear
  • Sulfonamides
  • Thiazolidinediones
  • Transcription Factors
  • bcl-2-Associated X Protein
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • ciglitazone