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Mechanism of inhibition of tumor angiogenesis by beta-hydroxyisovalerylshikonin
- Source :
- Cancer science. 100(2)
- Publication Year :
- 2009
-
Abstract
- Shikonin and beta-hydroxyisovalerylshikonin (beta-HIVS) from Lithospermum erythrorhizon inhibit angiogenesis via inhibition of vascular endothelial growth factor receptors (VEGFR) in an adenosine triphosphate-non-competitive manner, although the underlying molecular mechanism has not been fully understood. In the present study, we found that beta-HIVS inhibited angiogenesis within chicken chorioallantoic membrane approximately threefold more efficiently than shikonin. beta-HIVS also significantly inhibited angiogenesis in two other assays, induced either by Lewis lung carcinoma cells implanted in mouse dorsal skin or by VEGF in s.c. implanted Matrigel plugs and metastasis of Lewis lung carcinoma cells to lung. Therefore, using beta-HIVS as a bioprobe, we investigated the molecular mechanism of shikonin's anti-angiogenic actions. beta-HIVS inhibited the phosphorylation and expression of VEGFR2 and Tie2 without affecting VEGFR1 and fibroblast growth factor receptor 1 levels. beta-HIVS suppressed the phosphorylation but not the expression of extracellular signal-regulated kinase, and an Sp1-dependent transactivation of the VEGFR2 and Tie2 promoters, thereby suppressing the proliferation of vascular endothelial and progenitor cells. This was mimicked by an Sp1 inhibitor mithramycin A and partially rescued by Sp1 overexpression. These results implicate potential use of shikonin and beta-HIVS as leading compounds for clinical application in the future by virtue of their unique properties including: (i) inhibition of VEGFR2 and Tie2 phosphorylation in an adenosine triphosphate-non-competitive manner; (ii) simultaneous inhibition of the phosphorylation and expression of VEGFR2 and Tie2; and (iii) bifunctional inhibition of the growth in endothelial cells and vascular remodeling.
- Subjects :
- Vascular Endothelial Growth Factor A
Cancer Research
Angiogenesis
Blotting, Western
Angiogenesis Inhibitors
Apoptosis
Electrophoretic Mobility Shift Assay
Biology
Transfection
Chorioallantoic Membrane
Immunoenzyme Techniques
chemistry.chemical_compound
Carcinoma, Lewis Lung
Mice
Cell Movement
Cell Adhesion
Animals
Immunoprecipitation
RNA, Messenger
Phosphorylation
Luciferases
Cells, Cultured
Cell Proliferation
Matrigel
Vascular Endothelial Growth Factor Receptor-1
Neovascularization, Pathologic
Reverse Transcriptase Polymerase Chain Reaction
Fibroblast growth factor receptor 1
Lewis lung carcinoma
General Medicine
Vascular Endothelial Growth Factor Receptor-2
Cell biology
Vascular endothelial growth factor
Mice, Inbred C57BL
Chorioallantoic membrane
Oncology
chemistry
Biochemistry
cardiovascular system
Female
Signal transduction
Chickens
Drugs, Chinese Herbal
Naphthoquinones
Signal Transduction
Subjects
Details
- ISSN :
- 13497006
- Volume :
- 100
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cancer science
- Accession number :
- edsair.doi.dedup.....74efd7061543a32558203de35cd3ffbc