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Multifunctional anti-angiogenic activity of the cyclic peroxide ANO-2 with antitumor activity
Kazuhito Arakawa1, Yoshio Endo, Masashi Kimura
1Department of Experimental Therapeutics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
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 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.
Insights
ANO-2, a novel ozonide, effectively inhibits urokinase-type plasminogen activator (u-PA) production and angiogenesis. This potent anti-angiogenic drug also suppresses tumor growth and metastasis in preclinical models.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Angiogenesis is crucial for tumor growth and metastasis.
- Inhibition of urokinase-type plasminogen activator (u-PA) and cathepsins are potential anti-angiogenic strategies.
- Ozonides represent a class of compounds with potential therapeutic applications.
Purpose of the Study:
- To develop a novel anti-angiogenic drug targeting urokinase-type plasminogen activator (u-PA) production.
- To screen ozonides for inhibitory activity against u-PA production and angiogenesis.
- To evaluate the efficacy of a lead compound, ANO-2, in preclinical models of cancer.
Main Methods:
- Screening of 13 ozonides for inhibition of u-PA production in HT-1080 cells and angiogenesis in chicken embryos.
- In vitro assays using human umbilical vein endothelial cells (HUVECs) to assess tube formation.
- In vivo studies including mouse dorsal air sac assay for angiogenesis and Lewis lung carcinoma model for tumor growth and metastasis.
Main Results:
- Seven of 13 ozonides inhibited both u-PA production and angiogenesis.
- ANO-2 demonstrated potent inhibition of cathepsin B and u-PA production (IC50 = 0.47 microM).
- ANO-2 inhibited HUVEC tube formation, angiogenesis in vivo, primary tumor growth, and reduced pulmonary metastases without cytotoxicity.
Conclusions:
- ANO-2 is a potent, multifunctional anti-angiogenic agent with potential as a novel cancer therapeutic.
- ANO-2's mechanism involves inhibition of u-PA production and cathepsin activity.
- Preclinical data support the further development of ANO-2 for cancer treatment.