Multifunctional anti‐angiogenic activity of the cyclic peroxide ano‐2 with antitumor activity

Abstract

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 M) 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.

Synthesis, characterization, thermal behavior, and biological activity of ozonides from vegetable oils

“…These compounds probably generate oxygen reactive species (ROS) that cause apoptosis by induced oxidative stress. 57 Arakawa et al 58 reported that ozonide (cyclic peroxide) exhibits multiantiangiogenic and potent antitumor activity in vitro and in vivo against human fibrosarcoma HT-1080 cells. However, no data were found regarding the antitumor properties of ozonated oils.…”

Dipalmitoylation of radicicol results in improved efficacy against tumor growth and angiogenesis in vivo

“…This implies to us that microbial metabolites could provide an appealing treasury of effective angiogenesis inhibitors, (12) although compounds that are not derived from microorganisms might show antiangiogenic activity. (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) In fact several research groups, including ours, have shown that a number of seemingly unrelated classes of small molecules derived from microorganisms interfere with angiogenesis in in vitro and in vivo experimental models. (23)(24)(25)(26)(27) Our microbial inhibitors of angiogenesis include herbimycin, eponemycin, cytogenin and rhizoxin.…”