Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo.
Angiogenesis plays a key role in the development of malignant tumors. To clarify the roles of cyclooxygenase (COX) in malignant tumor development and angiogenesis, we investigated the effects of COX inhibitors on two kinds of gastrointestinal cancer xenograft, one of which overexpresses COX-2 and the other expresses no COX, in nude mice in vivo. There was a positive correlation between tumor volume and angiogenesis within the xenograft. Oral administration with a specific COX-2 or a nonspecific COX inhibitors lowered the expression of potent angiogenic factors; vascular endothelial growth factor and basic fibroblast growth factor, reduced angiogenesis and growth, induced apoptosis, and suppressed cell replication of the COX-2 overexpressing cancer xenografts in a dose-dependent manner. A nonspecific COX inhibitor, not a specific COX-2 inhibitor, reduced growth and angiogenesis of non-COX expressing cancer xenograft by inhibition of COX-1 in vascular endothelial cells. These results demonstrate that COX inhibitors suppress angiogenesis and tumor growth by inhibiting expression of angiogenic factors and vascular endothelial cell growth. They support the hypothesis that COX plays an important role in cancer growth via angiogenesis. These findings offer a new strategy against cancer using COX inhibitors (nonsteroidal anti-inflammatory drugs).
Sawaoka
H
H
Department of Internal Medicine and Therapeutics, Oska University Graduate School of Medicine, Suita, Japan.
Tsuji
S
S
Tsujii
M
M
Gunawan
E S
ES
Sasaki
Y
Y
Kawano
S
S
Hori
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use; D007527:Isoenzymes / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008854:Microscopy, Electron; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009578:Nitrobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D007213:Indomethacin