Abstract
Farnesiferol C (FC) is one of the major compounds isolated from Ferula assafoetida, an Asian herbal spice used for cancer treatment as a folk remedy. Here, we examined the hypothesis that novel antiangiogenic activities of FC contribute to anticancer efficacy. In human umbilical vein endothelial cells (HUVEC), exposure to the 10 to 40 mumol/L concentration range of FC inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, invasion, tube formation, and the expression of matrix metalloproteinase-2. In addition, FC inhibited the angiogenic sprouting of VEGF-treated rat aorta in an ex vivo model. Furthermore, FC inhibited the in vivo growth of mouse Lewis lung cancer allograft model by 60% (P < 0.001) at a daily i.p. dosage of 1 mg/kg body weight without any negative effect on the weight of the host mice. Immunohistochemistry staining showed decreased microvessel density (CD34) and proliferative index (Ki-67) without affecting the apoptotic (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) index. Mechanistically, FC decreased the binding of VEGF to VEGFR1/Flt-1, but not to VEGFR2/KDR/Flk-1. In terms of early signaling, FC exerted a rapid inhibitory action (examined within 10 minutes) on VEGF-induced autophosphorylation of VEGFR1 without affecting that of VEGFR2. Nevertheless, FC decreased the phosphorylation of most of the kinases downstream of VEGFR2: focal adhesion kinase, Src, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-jun-NH(2)-kinase without affecting AKT. Computer simulation suggests that FC may inhibit Src or focal adhesion kinase protein activities directly through its docking to their ATP-binding sites. Taken together, the multitargeting actions of FC, particularly VEGFR1 inhibition, may make it a novel drug candidate to complement current VEGF/VEGFR2-targeting antiangiogenic modalities for cancer.
Highlights
IntroductionFarnesiferol C (FC) is one of the sesquiterpene coumarin compounds isolated from the resin of Ferula assafoetida L., which is used as a food spice in many Asian countries and for the treatment of asthma, bronchitis, ulcer, kidney
Farnesiferol C (FC) is one of the sesquiterpene coumarin compounds isolated from the resin of Ferula assafoetida L., which is used as a food spice in many Asian countries and for the treatment of asthma, bronchitis, ulcer, kidneyAuthors' Affiliations: 1Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University and 2College of Pharmacy, National Core Research Center for Cell Signaling and Drug Discovery, Ewha Womans University, Seoul, Korea; 3The Hormel Institute, University of Minnesota, Austin, Minnesota; and 4Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, KoreaNote: Supplementary material for this article is available at Molecular Cancer Therapeutics Online.J
Effect of FC on Tumor Growth In vivo Prompted by the in vitro and ex vivo data supporting a potential antiangiogenic activity of FC, we examined the in vivo efficacy of FC on the growth of mouse Lewis lung cancer (LLC) allograft, which is highly dependent on angiogenesis
Summary
Farnesiferol C (FC) is one of the sesquiterpene coumarin compounds isolated from the resin of Ferula assafoetida L., which is used as a food spice in many Asian countries and for the treatment of asthma, bronchitis, ulcer, kidney. Authors' Affiliations: 1Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University and 2College of Pharmacy, National Core Research Center for Cell Signaling and Drug Discovery, Ewha Womans University, Seoul, Korea; 3The Hormel Institute, University of Minnesota, Austin, Minnesota; and 4Korea Research Institute of Chemical Technology, Yuseong-gu, Daejeon, Korea. Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). J. Lü holds a Kyung Hee University Infsternational Scholar travel award, 2009 to 2010. Choi contributed to this work and should be considered co-first authors
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