Etodolac inhibits EBER expression and induces Bcl-2-regulated apoptosis in Burkitt's lymphoma cells.
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.
Kobayashi
Miki
M
Department of Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan. abe-miki@hama-med.ac.jp
Nakamura
Satoki
S
Shibata
Kiyoshi
K
Sahara
Naohi
N
Shigeno
Kazuyuki
K
Shinjo
Kaori
K
Naito
Kensuke
K
Ohnishi
Kazunori
K
D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D017931:DNA Primers; D017308:Etodolac / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000077239:Meloxicam; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; C099537:Epstein-Barr virus encoded RNA 1; C106732:Epstein-Barr virus encoded RNA 2; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012367:RNA, Viral; D013843:Thiazines; D013844:Thiazoles; D017308:Etodolac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077239:Meloxicam