Etodolac inhibits EBER expression and induces Bcl-2-regulated apoptosis in Burkitt's lymphoma cells

Eur J Haematol. 2005 Sep;75(3):212-20. doi: 10.1111/j.1600-0609.2005.00498.x.


Cyclooxygenase-2 (COX-2) is reported to be an important cellular target for therapy in malignancies. The growth inhibitory effects of COX-2 inhibitors on malignancies have been demonstrated to be through not only COX-2 dependent, but also independent mechanisms. In this study, we showed that etodolac, COX-2 inhibitor, induced apoptosis via COX-2 independent pathway, and investigated the molecular details of etodolac-induced apoptosis in Burkitt's lymphoma cells. In Daudi and Raji Burkitt's lymphoma cell lines, which expressed no COX-2 enzyme, etodolac more strongly induced apoptosis compared to meloxicam. Moreover, etodolac did not induce apoptosis to normal B-lymphocytes. For the pathway of etodolac-induced apoptosis, reduction of anti-apoptotic bcl-2 mRNA and Bcl-2 protein, activation of Caspase-9 and -3, down-regulation of caspase inhibitors, c-IAP-1 and Survivin were involved. Moreover, EBER-1 and -2 expression in Epstein-Barr virus positive Daudi and Raji cells were reduced to result in down-regulation of Bcl-2 by treatment with etodolac. It has been reported that etodolac has stereoisomers, R- and S-etodolac. We found that racemate of etodolac more strongly induced apoptosis in Daudi and Raji cells compared to R- or S-etodolac. In conclusion, our findings indicated etodolac inhibited EBERs expression and induced apoptosis via a Bcl-2-regulated pathway. Moreover, racemate of etodolac more effectively induced apoptosis than R- and/or S-etodolac. Therefore, these activities of etodolac potentially extend to the treatment of patients with Burkitt's lymphoma resistant to chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Base Sequence
  • Blotting, Western
  • Burkitt Lymphoma / enzymology
  • Burkitt Lymphoma / genetics*
  • Burkitt Lymphoma / pathology*
  • Caspase 3
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • DNA Primers
  • Etodolac / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Meloxicam
  • Membrane Proteins
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • RNA, Messenger / genetics
  • RNA, Viral / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thiazines / pharmacology
  • Thiazoles / pharmacology


  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • DNA Primers
  • Epstein-Barr virus encoded RNA 1
  • Epstein-Barr virus encoded RNA 2
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • RNA, Viral
  • Thiazines
  • Thiazoles
  • Etodolac
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Meloxicam