Overexpression of cyclooxygenase-2 in childhood ependymomas: role of COX-2 inhibitor in growth and multi-drug resistance in vitro.
The management of ependymomas remains one of the most frustrating issues in pediatric neuro-oncology. Gross total resection is not always possible, and intensive chemotherapy and craniospinal radiotherapy have made no clear advances. Moreover, the chemoresistance of ependymomas may be explained by the expression of membrane transport molecule P-glycoprotein (P-gp). In this study the expression of cyclooxygenase 2 (COX-2) and the role of the specific COX-2 inhibitor NS-398 in growth and multi-drug resistance of ependymomas were investigated. COX-2 protein expression was assessed in 19 ependymomas immunohistochemically, and the effect of NS-398 on growth and multi-drug resistance was investigated using two primary cultured ependymoma cell lines. COX-2 protein expression was observed in 15 (79%) of the 19 ependymomas. NS-398 was found to reduce the proliferation of monolayer cell cultures in a dose- and time-dependent manner and to induce apoptosis and lower bcl-2 protein levels. After NS-398 treatment, Western blotting showed reduced P-gp expression and a rhodamine 123 efflux assay demonstrated a significant decrease in P-gp activity. Our findings demonstrate that COX-2 is overexpressed in ependymomas and that NS-398 is able to induce apoptosis and suppress P-gp expression and activity.
Kim
Seung-Ki
SK
Department of Neurosurgery, Cancer Research Institute, Seoul National University Hospital, Seoul, Korea.
Lim
Su-Young
SY
Wang
Kyu-Chang
KC
Kim
Young-Yim
YY
Chi
Je G
JG
Choi
Yoon La
YL
Shin
Hyung Jin
HJ
Cho
Byung-Kyu
BK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D004396:Coloring Agents / Q000494:pharmacology; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004806:Ependymoma / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D020112:Rhodamine 123 / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017304:Annexin A5; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D020112:Rhodamine 123; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases