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

• Published in: European journal of haematology 2005-09, Vol.75 (3), p.212-220
• Main Authors: Kobayashi, Miki, Nakamura, Satoki, Shibata, Kiyoshi, Sahara, Naohi, Shigeno, Kazuyuki, Shinjo, Kaori, Naito, Kensuke, Ohnishi, Kazunori
• Format: Article
• Language: English
• Subjects: apoptosis; Apoptosis - genetics; Base Sequence; Bcl-2; Blotting, Western; Burkitt Lymphoma - enzymology; Burkitt Lymphoma - genetics; Burkitt Lymphoma - pathology; Burkitt's lymphoma cells; Caspase 3; Caspases - metabolism; cell cycle; Cell Line, Tumor; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; DNA Primers; EBERs; Etodolac; Etodolac - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Membrane Proteins; Prostaglandin-Endoperoxide Synthases - genetics; Proto-Oncogene Proteins c-bcl-2 - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Viral - genetics; Thiazines - pharmacology; Thiazoles - pharmacology
• ISSN: 0902-4441; 1600-0609
• 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.