Combination of cyclooxygenase-2 inhibitors and oxaliplatin increases the growth inhibition and death in human colon cancer cells

Biochem Pharmacol. 2005 Sep 1;70(5):658-67. doi: 10.1016/j.bcp.2005.05.028.

Abstract

The cyclooxygenase-2 (COX-2) protein is highly expressed in a variety of human cancers and has been reported to promote tumor growth. Non-steroidal anti-inflammatory drugs such as etodolac and celecoxib have been shown to inhibit COX-2 activity and may play a role in the chemoprevention of cancer. Oxaliplatin is a third-generation platinum compound that exhibits a different spectrum of activity compared with cisplatin. Other cisplatin-resistant tumors can still respond to oxaliplatin. However, the anticancer ability of the combination of COX-2 inhibitors and oxaliplatin is still unknown. In this study, we investigated the effects of combination of COX-2 inhibitors and oxaliplatin on the cell growth and survival in human colon cancer cells. Treatments with etodolac (0.3-0.5 mM) or celecoxib (20-80 microM) for 24 h concentration-dependently induced the cytotoxicity in the RKO colon carcinoma cells. Etodolac and celecoxib did not alter the COX-2 protein levels but inhibited its enzyme activity to reduce prostaglandin E2 production. Furthermore, the cell survival was concentration-dependently decreased following oxaliplatin (1-100 microM, 24 h) treatment. Combination of oxaliplatin and etodolac additively increased the death and growth inhibition of RKO cells. Survivin, an inhibitor protein of apoptosis, mediates anti-apoptosis and promotes cell division in cancer cells. Oxaliplatin or COX-2 inhibitors significantly decreased the levels of survivin proteins. Moreover, survivin proteins were markedly diminished following co-treatment with oxaliplatin and etodolac. Together, this is the first report that combination of COX-2 inhibitors and oxaliplatin can increase the reduction of survivin protein expression, growth inhibition, and death in human colon cancer cells.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / chemistry
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / pathology
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Dinoprostone / biosynthesis
  • Drug Synergism
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins / analysis
  • Neoplasm Proteins / analysis
  • Organoplatinum Compounds / pharmacology*
  • Oxaliplatin
  • Prostaglandin-Endoperoxide Synthases / analysis
  • Survivin

Substances

  • BIRC5 protein, human
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Inhibitor of Apoptosis Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Organoplatinum Compounds
  • Survivin
  • Oxaliplatin
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone