Herbal compound farnesiferol C exerts antiangiogenic and antitumor activity and targets multiple aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) signaling cascades

Jae Ho Lee, Sun Choi, Yoonji Lee, Hyo Jeong Lee, Kwan Hyun Kim, Kyoo Seok Ahn, Hyunsoo Bae, Hyo Jung Lee, Eun Ok Lee, Kwang Seok Ahn, Shi Yong Ryu, Junxuan Lü, Sung Hoon Kim

Research output: Contribution to journalArticle

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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 ìmol/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-NH2-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.

Original languageEnglish (US)
Pages (from-to)389-399
Number of pages11
JournalMolecular cancer therapeutics
Volume9
Issue number2
DOIs
StatePublished - Feb 2010

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Vascular Endothelial Growth Factor A
Focal Adhesion Protein-Tyrosine Kinases
Phosphotransferases
Ferula
farnesiferol C
Spices
Mitogen-Activated Protein Kinase 3
DNA Nucleotidylexotransferase
Mitogen-Activated Protein Kinase 1
Matrix Metalloproteinase 2
Human Umbilical Vein Endothelial Cells
Traditional Medicine
p38 Mitogen-Activated Protein Kinases
Microvessels
Computer Simulation
Cell Movement
Allografts
Aorta
Lung Neoplasms
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lee, Jae Ho ; Choi, Sun ; Lee, Yoonji ; Lee, Hyo Jeong ; Kim, Kwan Hyun ; Ahn, Kyoo Seok ; Bae, Hyunsoo ; Lee, Hyo Jung ; Lee, Eun Ok ; Ahn, Kwang Seok ; Ryu, Shi Yong ; Lü, Junxuan ; Kim, Sung Hoon. / Herbal compound farnesiferol C exerts antiangiogenic and antitumor activity and targets multiple aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) signaling cascades. In: Molecular cancer therapeutics. 2010 ; Vol. 9, No. 2. pp. 389-399.
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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 {\`i}mol/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-NH2-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.",
author = "Lee, {Jae Ho} and Sun Choi and Yoonji Lee and Lee, {Hyo Jeong} and Kim, {Kwan Hyun} and Ahn, {Kyoo Seok} and Hyunsoo Bae and Lee, {Hyo Jung} and Lee, {Eun Ok} and Ahn, {Kwang Seok} and Ryu, {Shi Yong} and Junxuan L{\"u} and Kim, {Sung Hoon}",
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Herbal compound farnesiferol C exerts antiangiogenic and antitumor activity and targets multiple aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) signaling cascades. / Lee, Jae Ho; Choi, Sun; Lee, Yoonji; Lee, Hyo Jeong; Kim, Kwan Hyun; Ahn, Kyoo Seok; Bae, Hyunsoo; Lee, Hyo Jung; Lee, Eun Ok; Ahn, Kwang Seok; Ryu, Shi Yong; Lü, Junxuan; Kim, Sung Hoon.

In: Molecular cancer therapeutics, Vol. 9, No. 2, 02.2010, p. 389-399.

Research output: Contribution to journalArticle

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T1 - Herbal compound farnesiferol C exerts antiangiogenic and antitumor activity and targets multiple aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) signaling cascades

AU - Lee, Jae Ho

AU - Choi, Sun

AU - Lee, Yoonji

AU - Lee, Hyo Jeong

AU - Kim, Kwan Hyun

AU - Ahn, Kyoo Seok

AU - Bae, Hyunsoo

AU - Lee, Hyo Jung

AU - Lee, Eun Ok

AU - Ahn, Kwang Seok

AU - Ryu, Shi Yong

AU - Lü, Junxuan

AU - Kim, Sung Hoon

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N2 - 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 ìmol/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-NH2-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.

AB - 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 ìmol/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-NH2-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.

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