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Dienogest, a synthetic steroid, suppresses both embryonic and tumor-cell-induced angiogenesis
M Nakamura1, Y Katsuki, Y Shibutani
1Department of Molecular Oncology, The Tokyo Metropolitan Institute of Medical Science (Rinshoken), Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome Bunkyo-ku, Tokyo, Japan.
Abstract:
Orally administered dienogest (17alpha-cyanomethyl-17beta-hydroxy-estra-4,9-diene-3-one) is efficacious against human hormone-dependent cancer xenografts in severely immunodeficient mice and in rats with experimental endometriosis, but its mechanisms of action remain unclear. We assessed the effect of dienogest on angiogenesis, because these two diseases that are sensitive to dienogest are known to be angiogenesis-dependent. Topical dienogest treatment dose-dependently inhibited embryonic angiogenesis, the ID(50) value being 6.4 nmol/egg. Oral administration of dienogest (1 mg kg(-1) day(-1)) for 5 consecutive days significantly suppressed angiogenesis induced by S-180 mouse tumor cells in the mouse dorsal air sac assay. In vitro experiments showed that dienogest at concentrations up to 10 microM had little or no effect on the proliferation of plasminogen activator activity or formation of tube-like structures by microvascular endothelial cells. These results suggest that dienogest is a new, orally active antagonist of angiogenesis, and that its anti-angiogenic action may be involved in its therapeutic effects on cancer xenografts and endometriosis that we observed previously.
Insights
Dienogest, an oral medication, effectively inhibits angiogenesis, the process of new blood vessel formation. This anti-angiogenic action may explain its therapeutic benefits in treating endometriosis and hormone-dependent cancers.
Area of Science:
- Pharmacology
- Oncology
- Reproductive Biology
Background:
- Dienogest is effective against hormone-dependent cancers and endometriosis.
- The precise mechanisms of dienogest's action are not fully understood.
- Both cancer and endometriosis are angiogenesis-dependent diseases.
Purpose of the Study:
- To investigate the effect of dienogest on angiogenesis.
- To determine if dienogest's anti-angiogenic properties contribute to its therapeutic efficacy.
Main Methods:
- Assessed the dose-dependent inhibition of embryonic angiogenesis by topical dienogest.
- Evaluated the effect of orally administered dienogest on tumor-induced angiogenesis in a mouse model.
- Conducted in vitro experiments on endothelial cell proliferation and tube formation.
Main Results:
- Topical dienogest inhibited embryonic angiogenesis with an ID(50) of 6.4 nmol/egg.
- Oral dienogest significantly suppressed tumor-induced angiogenesis in vivo.
- In vitro, dienogest showed minimal impact on endothelial cell proliferation and tube formation at tested concentrations.
Conclusions:
- Dienogest acts as an orally active antagonist of angiogenesis.
- The anti-angiogenic effects of dienogest likely contribute to its efficacy in treating cancer xenografts and endometriosis.