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

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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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ACKNOWLEDGMENTS

This work was supported by Medical Research Center (MRC) grant (No. 2009-0063466) (S.H. Kim) and Hormel Foundation and NIH grant CA136953 (J. Lu). All authors declare no personal or financial conflict of interests.

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Authors and Affiliations

  1. College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul, 130-701, Republic of Korea

    Kwan-Hyun Kim, Hyo-Jung Lee, Soo-Jin Jeong, Hyo-Jeong Lee, Eun-Ok Lee & Sung-Hoon Kim

  2. The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, Minnesota, 55912, USA

    Kwan-Hyun Kim, Yong Zhang, Junxuan Lü & Sung-Hoon Kim

  3. College of Medicine, Yonsei University, Seoul, 120-752, Republic of Korea

    Hyun-Seok Kim

  4. Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, 305-600, Republic of Korea

    Shi-Yong Ryu

  5. College of Life Sciences, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Min-Ho Lee

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  1. Kwan-Hyun Kim
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Correspondence to Junxuan Lü or Sung-Hoon Kim.

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Kim, KH., Lee, HJ., Jeong, SJ. et al. Galbanic Acid Isolated from Ferula assafoetida Exerts In Vivo Anti-tumor Activity in Association with Anti-angiogenesis and Anti-proliferation. Pharm Res 28, 597–609 (2011). https://doi.org/10.1007/s11095-010-0311-7

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