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Research ArticleDrug Discovery and Translational Medicine

Anacardic Acid (6-Pentadecylsalicylic Acid) Inhibits Tumor Angiogenesis by Targeting Src/FAK/Rho GTPases Signaling Pathway

Yuanyuan Wu, Lijun He, Li Zhang, Jing Chen, Zhengfang Yi, Jian Zhang, Mingyao Liu and Xiufeng Pang
Journal of Pharmacology and Experimental Therapeutics November 2011, 339 (2) 403-411; DOI: https://doi.org/10.1124/jpet.111.181891
Yuanyuan Wu
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Lijun He
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Li Zhang
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Jing Chen
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Zhengfang Yi
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Jian Zhang
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Mingyao Liu
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Xiufeng Pang
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Abstract

Anacardic acid (6-pentadecylsalicylic acid), a natural inhibitor of histone acetyltransferase from Amphipterygium adstringens, has been shown to have anti-inflammatory, anticancer, antioxidative, and antimicrobial functions. However, whether this salicylic acid could block angiogenesis has not been elucidated to date. Here, we postulate that anacardic acid affects multiple steps of tumor angiogenesis to contribute to tumor inhibition. In this study, we found that vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and adhesion and capillary-like structure formation of primary cultured human umbilical vascular endothelial cells (HUVECs) could all be significantly suppressed by anacardic acid in vitro, without detectable cellular toxicity. Furthermore, anacardic acid effectively inhibited vascular development in chick embryo chorioallantoic membrane ex vivo (n = 10) and VEGF-triggered corneal neovascularization in vivo (n = 10). A mechanistic study revealed that anacardic acid blocked activities of Src and FAK kinases in concentration- and time-dependent manners in HUVECs, resulting in activation of RhoA-GTPase and inactivation of Rac1- and Cdc42-GTPases. Of note, when anacardic acid (2 mg/kg per day) was subcutaneously administrated to mice bearing human prostate tumor xenografts (n = 6–7), the volume and weight of solid tumors were significantly retarded. Src, Ki-67, and CD31 immunohistochemical staining further revealed that Src protein expression, tumor cell proliferation, and microvessel density could be remarkably suppressed by anacardic acid. Taken together, our findings demonstrate for the first time that anacardic acid functions as a potent tumor angiogenesis inhibitor by targeting the Src/FAK/Rho GTPase signaling pathway, leading to significant suppression of prostate tumor growth.

Footnotes

  • This work is supported by the Fundamental Research Funds for the Central Universities [Grant 78210021]; the Chenguang Program of Shanghai Municipal Education Commission [Grant 10CG25] (to X.P.); the Research Platform for Cell Signaling Networks [Grant 06DZ22923] (to M.L.); and the Science and Technology Commission of Shanghai Municipality [Grant 09PJ1403900] (to M.L.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.181891.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    VEGF
    vascular endothelial growth factor
    Src
    steroid receptor coactivator
    FAK
    focal adhesion kinase
    AZD0530
    N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine
    SKI-606
    4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile
    DMSO
    dimethyl sulfoxide
    NIH
    National Institutes of Health
    VEGFR
    vascular endothelial growth factor receptor
    HUVEC
    human umbilical vein endothelial cell
    ECM
    endothelial cell culture medium
    FBS
    fetal bovine serum
    p
    phospho
    CAM
    chick embryo chorioallantoic membrane.

  • Received March 21, 2011.
  • Accepted August 8, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 2
1 Nov 2011
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Research ArticleDrug Discovery and Translational Medicine

Anacardic Acid Inhibits Tumor Angiogenesis

Yuanyuan Wu, Lijun He, Li Zhang, Jing Chen, Zhengfang Yi, Jian Zhang, Mingyao Liu and Xiufeng Pang
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 403-411; DOI: https://doi.org/10.1124/jpet.111.181891

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Research ArticleDrug Discovery and Translational Medicine

Anacardic Acid Inhibits Tumor Angiogenesis

Yuanyuan Wu, Lijun He, Li Zhang, Jing Chen, Zhengfang Yi, Jian Zhang, Mingyao Liu and Xiufeng Pang
Journal of Pharmacology and Experimental Therapeutics November 1, 2011, 339 (2) 403-411; DOI: https://doi.org/10.1124/jpet.111.181891
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