19 天然物由来の新しい血管新生阻害剤の探索(口頭発表の部)

抄録

Angiogenesis is defined as the generation and growth of new blood vessels from pre-existing vessels. Angiogenic factors including basic Fibroblast Growth Factor (bFGF) and Vascular Endothelial Growth Factor (VEGF) stimulate endothelial cell proliferation. Sprouting endothelial cell break down the extracellular matrix, and then migrate to cancer cells, finally lumen is formed. Because tumor growth is depended on a blood supply (oxygen and nutrients), angiogenesis inhibitors may potentially be used as new therapeutic agents for cancer treatment. In connection with our studies on the isolation of angiogenesis inhibitor for development of new anti-cancer agents, we have investigated the anti-angiogenic activity of 200 medicinal plants and 120 marine invertebrates. Among them, the MeOH extractives from Saussurea lappa, Caesalpinia sappan, and Anemarrhena asphodeloides from medicinal plants, and the EtOH extractives from the bryozoan Dakaria subovoidea and the sponge Haliclona olivacea from marine invertebrates showed inhibitory effect on BAECs proliferation. Further investigation has led to the isolation of eight anti-angiogenic compounds (1-8). In the present studies, we have found that costunolide (3) and cis-hinokiresinol (4) selectively inhibit bFGF or VEGF-induced endothelial cells proliferation and migration. From these results, we hypothesized that costunolide and cis-hinokiresinol would inhibit angiogenesis by blockade of angiogenic factors signaling pathway. To be anticipated, costunolide and cis-hinokiresinol inhibited the VEGF KDR/Flk-1 tyrosine phosphorylation. Moreover, cis-hinokiresinol reduced the vessel growth induced by VEGF in mouse corneal neovascularization model. Compounds 5-8 isolated from marine invertebrates inhibited BAECs proliferation. Among them, compounds 6 and 8 inhibited bFGF-induced BAECs mitogenesis more selectively in a dose dependent manner.