Multifunctional anti-angiogenic activity of the cyclic peroxide ANO-2 with antitumor activity.
Our focus was to develop an anti-angiogenic drug possessing the inhibitory activity of urokinase-type plasminogen activator (u-PA) production. During preliminary screening, the effects of 13 ozonides on the inhibition of u-PA production in human fibrosarcoma HT-1080 cells and on the inhibition of angiogenesis on chicken embryonic chorioallantoic membranes were determined. Of the ozonides tested, 9 inhibited in vitro u-PA production of HT-1080 cells and 7 of these 9 exhibited strong anti-angiogenic activity. Interestingly, 6 of the 13 ozonides also inhibited cathepsin B activity. 1-Phenyl-1, 4-epoxy-1H,4H-naphtho[1,8-de][1, 2]dioxepin (ANO-2) potently inhibited cathepsin B (IC(50) = 0.47 microM) as well as u-PA production. Consequently, ANO-2 was selected for further study. ANO-2 inhibited tube formation by human umbilical vein endothelial cells cultured on Matrigel while exhibiting no cytotoxicity. Additionally, in vivo administration of ANO-2 inhibited angiogenesis induced by mouse Sarcoma-180 cells tested using the mouse dorsal air sac assay. Moreover, ANO-2 also suppressed primary tumor growth and reduced the number of pulmonary metastases caused by Lewis lung carcinoma cells in mice. These in vitro and in vivo activities indicate that ANO-2 has considerable potential as a new and potent anti-angiogenic drug that inhibits both u-PA production and enzymatic activity of cathepsins, indicating that ANO-2 may be a multifunctional inhibitor of angiogenesis.
Department of Experimental Therapeutics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Kazuhito
K
Arakawa
Yoshio
Y
Endo
Masashi
M
Kimura
Takanori
T
Yoshida
Takeshi
T
Kitaoka
Tomoyasu
T
Inakazu
Yuji
Y
Nonami
Manabu
M
Abe
Araki
A
Masuyama
Masatomo
M
Nojima
Takuma
T
Sasaki
D000400:Air Sacs / Q000098:blood supply; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000517:prevention & control; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002642:Chick Embryo; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010082:Oxepins / Q000138:chemical synthesis / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D012509:Sarcoma / Q000098:blood supply / Q000517:prevention & control; D014471:Umbilical Veins / Q000166:cytology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000652:urine; D023041:Xenograft Model Antitumor Assays
C461941:1-phenyl-1,4-epoxy-1H,4H-naphtho(1,8-de)(1,2)dioxepin; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D009281:Naphthalenes; D010082:Oxepins; D012333:RNA, Messenger; D012259:Ribonuclease, Pancreatic; D014568:Urokinase-Type Plasminogen Activator; D002401:Cathepsin B