Potent inhibition of in vivo angiogenesis and tumor growth by a novel cyclooxygenase-2 inhibitor, enoic acanthoic acid.
Recent studies have shown that cyclooxygenase-2 is crucially involved in angiogenesis. In fact, several specific cyclooxygenase-2 inhibitors suppress angiogenesis in vivo, suggesting that cyclooxygenase-2 is a promising target for the treatment of angiogenesis-related diseases. In the present study we investigate the activity of a new cyclooxygenase-2 inhibitor, enoic acanthoic acid (EAA), which was synthesized from the known natural cyclooxygenase-2 inhibitor, acanthoic acid (AA). The demonstration of a high correlation between EAA- and celecoxib-induced gene expression signatures in microarray experiments validated the specificity of EAA on cyclooxygenase-2. In angiogenesis assays, EAA potently inhibited basic fibroblast growth factor-induced invasion and tube formation of bovine aortic endothelial cells in vitro. Moreover, this inhibitor prevented both neovascularization of the chorioallantoic membrane of growing chick embryo and basic fibroblast growth factor-induced mouse corneal angiogenesis in vivo. EAA also significantly suppressed the growth of bladder tumors in a mouse model, showing better antitumor activity than celecoxib. Furthermore, gelatin zymogram analysis revealed that EAA potently inhibited the activities of matrix metalloproteinase 2 and 9. These results clearly demonstrate that EAA is a promising agent for the prevention and treatment of angiogenesis-related diseases including cancer.
Jung
Hye Jin
HJ
Department of Biotechnology, College of Engineering, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749, Korea.
Shim
Joong Sup
JS
Suh
Young-Ger
YG
Kim
Young-Myeong
YM
Ono
Mayumi
M
Kwon
Ho Jeong
HJ
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004224:Diterpenes / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D005354:Fibrosarcoma / Q000098:blood supply*; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008861:Microsomes / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011817:Rabbits
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004224:Diterpenes; C099958:acanthoic acid; D016222:Fibroblast Growth Factor 2; D051545:Cyclooxygenase 1