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

Miki Kobayashi1, Satoki Nakamura, Kiyoshi Shibata

  • 1Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan. abe-miki@hama-med.ac.jp

European Journal of Haematology
|August 18, 2005
PubMed

Insights

Etodolac, a cyclooxygenase-2 (COX-2) inhibitor, induces apoptosis in Burkitt

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclooxygenase-2 (COX-2) is a key target in cancer therapy.
  • COX-2 inhibitors can exert anti-cancer effects through COX-2 dependent and independent pathways.
  • Burkitt's lymphoma is an aggressive B-cell non-Hodgkin lymphoma.

Purpose of the Study:

  • To investigate the COX-2 independent apoptosis-inducing effects of etodolac in Burkitt's lymphoma cells.
  • To elucidate the molecular mechanisms underlying etodolac-induced apoptosis.
  • To compare the efficacy of etodolac's stereoisomers in inducing apoptosis.

Main Methods:

  • Treatment of Burkitt's lymphoma cell lines (Daudi, Raji) and normal B-lymphocytes with etodolac and meloxicam.
  • Analysis of apoptosis markers, including Bcl-2 mRNA and protein levels, Caspase-9 and -3 activation, and levels of c-IAP-1 and Survivin.
  • Assessment of Epstein-Barr virus-encoded RNA (EBER-1 and -2) expression.
  • Comparison of apoptosis induction by racemic etodolac versus its R- and S-stereoisomers.

Main Results:

  • Etodolac induced apoptosis in COX-2 negative Burkitt's lymphoma cells, but not in normal B-lymphocytes.
  • Apoptosis was mediated by down-regulation of anti-apoptotic Bcl-2, activation of Caspase-9 and -3, and reduced levels of c-IAP-1 and Survivin.
  • Etodolac treatment reduced EBER-1 and -2 expression, leading to Bcl-2 down-regulation.
  • Racemic etodolac demonstrated stronger apoptosis induction than R- or S-etodolac.

Conclusions:

  • Etodolac induces apoptosis in Burkitt's lymphoma cells via a COX-2 independent pathway.
  • The mechanism involves inhibition of EBERs expression and subsequent Bcl-2 down-regulation, leading to caspase activation.
  • Racemic etodolac is more effective than its individual stereoisomers, suggesting potential for treating chemotherapy-resistant Burkitt's lymphoma.

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