Galbanic Acid Isolated from Ferula assafoetida Exerts In Vivo Anti-tumor Activity in Association with Anti-angiogenesis and Anti-proliferation

Author： Kim Kwan-Hyun Lee Hyo-Jung Jeong Soo-Jin Lee Hyo-Jeong Lee Eun-Ok Kim Hyun-Seok Zhang Yong Ryu Shi-Yong Lee Min-Ho Lü Junxuan Kim Sung-Hoon

Publisher： Springer Publishing Company

ISSN： 0724-8741

Source： Pharmaceutical Research, Vol.28, Iss.3, 2011-03, pp. : 597-609

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Abstract

To investigate whether galbanic acid (GBA) exerts anti-angiogenic and anti-cancer activities.Using human umbilical vein endothelial cell (HUVEC) model, we analyzed effects of GBA on cellular and molecular events related to angiogenesis. We tested its direct anti-proliferative action on mouse Lewis lung cancer (LLC) cells and established its in vivo anti-angiogenic and anti-tumor efficacy using LLC model.GBA significantly decreased vascular endothelial growth factor (VEGF)-induced proliferation and inhibited VEGF-induced migration and tube formation of HUVECs. These effects were accompanied by decreased phosphorylation of p38-mitogen-activated protein kinase (MAPK), c-jun N-terminal kinase (JNK), and AKT, and decreased expression of VEGFR targets endothelial nitric oxide synthase (eNOS) and cyclin D1 in VEGF-treated HUVECs. GBA also decreased LLC proliferation with an apparent G2/M arrest, but did not induce apoptosis. In vivo, inclusion of GBA in Matrigel plugs reduced VEGF-induced angiogenesis in mice. Galbanic acid given by daily i.p. injection (1 mg/kg) inhibited LLC-induced angiogenesis in an intradermal inoculation model and inhibited the growth of s.c. inoculated LLC allograft in syngenic mice. Immunohistochemistry revealed decreased CD34 microvessel density index and Ki-67 proliferative index in GBA-treated tumors.GBA exerts anti-cancer activity in association with anti-angiogenic and anti-proliferative actions.