Differential effects of selective COX-2 inhibitors on cell cyde regulation and proliferation of glioblastoma cell lines

Adel Kardosh, Martina Blumenthal, Wei Jun Wang, Thomas C. Chen, Axel H. Schönthal

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

It is well established that traditional NSAIDs, which inhibit cyclooxygenase (COX) 1 and COX-2, have the potential to reduce the risk of colorectel cancer. New generation COX inhibitors have been developed that selectively inhibit COX-2, which might cause less side effects while still retaining their therapeutic potential. As patients with brain tumors, such as glioblastoma, exhibit a very poor prognosis, we began to explore whether COX inhibitors could be useful for the treatment of this type of tumor. We found that celecoxib inhibited the proliferation of various glioblastoma cell lines in vitro much more potently than traditional NSAIDs. In addition, although several different selective COX-2 inhibitors potently reduced PGES levels in these cells, none of them exerted anti-proliferative effects that were comparable to celecoxib. The addition of external PGE2 to celecoxib-treated cells did not restore proliferation, indicating that growth inhibition by celecoxib was not mediated via the blockage of PGE2 production. In an effort to determine the underlying molecular processes that might mediate celecoxib's potent anti-proliferative effects, we found a loss of the activity of cyclin-dependent kinases, the essential regulators of cell proliferation, which was due to the transcriptional downregulation of cyclin A and cyclin B expression. Taken together, our results show that celecoxib exerts COX-2-independent anti-proliferative effects on glioblastoma cell growth, which are more potent than those of other selective COX-2 inhibitors or traditional NSAIDs, and which are mediated via the transcriptional inhibition of two essential components of the cell cycle machinery, cyclin A and cyclin B.

Original languageEnglish (US)
Pages (from-to)55-62
Number of pages8
JournalCancer Biology and Therapy
Volume3
Issue number1
DOIs
StatePublished - Jan 2004

Keywords

  • Bextra
  • CDK
  • Celebrex
  • Celecoxib
  • Cell cycle
  • Cyclin
  • Flurbiprofen
  • Indomethacin
  • Ketoprofen
  • NS-398
  • NSAIDs
  • Piroxicam
  • Rofecoxib
  • Sulindac
  • Valdecoxib
  • Vioxx

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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