Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398.
The up-regulation of cyclooxygenase 2 (COX-2) expression is a frequent occurrence in a variety of different tumors. In this study, COX-2 protein expression was investigated in 50 glioma and 3 normal brain specimens by immunohistochemistry. Expression of COX-2 protein was observed in all normal brain and glioma specimens by immunohistochemistry, regardless of histological grade. The immunoreactive score was significantly higher in high-grade glioma than low-grade glioma and normal brain specimens. For a subset of these tumors (nine gliomas and three normal brain), Western blot analysis was also performed. COX-2 protein was detected in all specimens by Western blot analysis. The effect of the specific COX-2 inhibitor NS-398 on monolayer cell cultures and three-dimensional glioma spheroids was investigated using U-87MG and U-251MG human glioblastoma cell lines. The proliferation rate was assessed in monolayer cultures. In addition, a growth assay, a migration assay, an apoptosis assay, and a tumor invasion assay were performed in a three-dimensional spheroid culture system. NS-398 was able to reduce the proliferation of monolayer cell cultures, as well as the growth of spheroids and tumor cell migration, in a dose-dependent manner. There was also a moderate increase in the number of apoptotic cells in the treated spheroids. NS-398 did not have an inhibitory effect on tumor invasion in the coculture spheroid system. Our study provides evidence that COX-2 is up-regulated in the majority of high-grade gliomas and that a potential role of COX-2 inhibitors as an adjuvant therapy for brain tumors may exist.
Joki
T
T
Brain Tumor Research Center, Brigham and Women's Hospital, The Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Heese
O
O
Nikas
D C
DC
Bello
L
L
Zhang
J
J
Kraeft
S K
SK
Seyfried
N T
NT
Abe
T
T
Chen
L B
LB
Carroll
R S
RS
Black
P M
PM
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001254:Astrocytoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D001921:Brain / Q000201:enzymology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006131:Growth Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases