Galbanic Acid Isolated from Ferula assafoetida Exerts In Vivo Anti-tumor Activity in Association with Anti-angiogenesis and Anti-proliferation |
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Authors: | Kwan-Hyun Kim Hyo-Jung Lee Soo-Jin Jeong Hyo-Jeong Lee Eun-Ok Lee Hyun-Seok Kim Yong Zhang Shi-Yong Ryu Min-Ho Lee Junxuan L�� Sung-Hoon Kim |
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Affiliation: | College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea. |
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Abstract: | Purpose To investigate whether galbanic acid (GBA) exerts anti-angiogenic and anti-cancer activities. Methods 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. Results 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. Conclusions GBA exerts anti-cancer activity in association with anti-angiogenic and anti-proliferative actions. |
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