Cyclooxygenase-2 level and culture conditions influence NS398-induced apoptosis and caspase activation in lung cancer cells

Oncol Rep. Nov-Dec 2001;8(6):1321-5. doi: 10.3892/or.8.6.1321.

Abstract

Cyclooxygenases (COXs) catalyze the synthesis of prostaglandins (PGs) from arachidonic acid. Overexpression of COX-2 is frequently found in human cancers and is suggested to play an important role in tumorigenesis. Recent studies indicated that COX-2 inhibitors exert potent anti-cancer effects on a number of cancers. Interestingly, some COX-2 inhibitors potently induce apoptosis, while other COX-2 inhibitors primarily induce growth inhibition. Therefore, there is a variability in the effects that different COX-2 inhibitors have on cancer cells. In this study, we demonstrated that induction of apoptosis of high COX-2-expressing A549 lung cancer cells by a specific COX-2 inhibitor NS398 was observed in cells cultured under serum-free condition. However, this drug induced G1 growth arrest rather than apoptosis in A549 cells maintained in 10% serum medium. Conversely, low COX-2-expressing H226 lung cancer cells were resistant to NS398-induced apoptosis under both serum-free and serum-containing conditions. Moreover, our results showed that NS398-induced apoptosis is associated with activation of caspase-3, a cysteine protease that plays a crucial role in the execution phase of apoptosis. These results suggest that the cytotoxic effect of COX-2 inhibitors on cancer cells may be influenced by extracellular environments and the anti-cancer action of these inhibitors in vivo needs careful evaluation. Additionally, a correlation between the level of COX-2 expression and the extent of apoptosis induced by COX-2 inhibitors was found.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Caspase 3
  • Caspases / metabolism*
  • Cell Cycle
  • Culture Media, Serum-Free
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism*
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / pathology
  • Membrane Proteins
  • Nitrobenzenes / pharmacology*
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Culture Media, Serum-Free
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Nitrobenzenes
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • CASP3 protein, human
  • Caspase 3
  • Caspases