A novel angiogenesis inhibitor: Adaphostin (NSC 680410)

4099 Angiogenesis is functionally defined as the sprouting of new blood vessels from pre-existing vasculature and consists of several distinct stages including endothelial cell proliferation, migration, invasion, and differentiation into new blood vessels. This process is essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a major angiogenic agent that regulates key steps of the angiogenesis process. Recent studies have reported that NSC 680410, an adamantyl congener of AG957 (NSC 680705) inhibits VEGF secretion and leukemic cell growth in sub-micromolar concentrations. Here, we describe the anti-proliferative, pro-apoptotic and anti-angiogenic activities of Adaphostin, (NSC 680410), and its water-soluble analog NSC 726814. Results from our laboratory indicate that Adaphostin (NSC 680410) is 3-7 fold more potent than its water-soluble analog NSC726814 in inhibiting endothelial cell growth, tube formation and VEGF induced migration. Adaphostin induces apoptosis in HUVEC at concentrations and exposure times at which the cells are refractory to NSC 726814. Since VEGF is essential for vasculogenesis and angiogenesis, we investigated the effect of adaphostin and NSC 726814 on VEGF secretion in endothelial cells. Unlike leukemia cells (where Adaphostin caused a decrease in VEGF levels), Adaphostin caused a marked increase (30-fold) in VEGF secretion into the media compared to untreated control or NSC726814 treated cells. This increase could be due to oxidative stress in the treated endothelial cells and needs further investigation. These findings suggest that Adaphostin (NSC 680410) is a potent anti-angiogenic inhibitor and may provide a means for therapeutic intervention in metastatic disease. These observations should aid in the design of future clinical trials of this novel agent.