Human mesothelioma samples overexpress both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS2): in vitro antiproliferative effects of a COX-2 inhibitor.
Accumulating data demonstrate overexpression of both inducible NO synthase (NOS2) and cyclooxygenase-2 (COX2) in many epithelial neoplasias. In addition, cyclooxygenase inhibitors have been shown to have antineoplastic and prophylactic efficacy against human colon cancer and in mouse models of this disease. Mesothelioma arises in a context of asbestos exposure and chronic inflammation, which would be expected to enhance the expression of these inducible enzymes. This study demonstrates that both inducible enzymes were expressed in 30 human mesothelioma tissues but were not detectable in nonreactive mesothelial tissues from the same individuals. In contrast, areas of reactive mesothelial cells stained positively for these enzymes. In vitro exposure of human mesothelioma cell lines to the COX2 inhibitor, NS398, revealed dose- and time-dependent antiproliferative activity, whereas the NOS2 inhibitor, 1400W, had no detectable inhibitory effect. Surprisingly, nonmalignant human mesothelial isolates expressed both NOS2 and COX2 in vitro at the same level as mesothelioma cell lines but were less sensitive to NS398 inhibition. This finding indicates that these nonmalignant isolates may retain properties of reactive mesothelial cells and suggests that targets in addition to COX2 may be involved in the antiproliferative response of mesothelioma cell lines. These results have clinical significance because of the selective activity of the drug coupled with the therapeutic resistance and poor prognosis of mesothelioma. The findings presented here suggest that further preclinical studies of these inhibitors in animal models of mesothelioma would be of great interest.
Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.
A
A
Marrogi
H I
HI
Pass
M
M
Khan
L J
LJ
Metheny-Barlow
C C
CC
Harris
B I
BI
Gerwin
D000328:Adult; D000368:Aged; D000578:Amidines / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001194:Asbestos / Q000009:adverse effects; D001596:Benzylamines / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000401:mortality; D008297:Male; D008565:Membrane Proteins; D008654:Mesothelioma / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000401:mortality; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000578:Amidines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001596:Benzylamines; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D001194:Asbestos; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases