Angiogenesis is one of the essential hallmarks of cancer, typically breast
cancer. Signaling from VEGFR-2 is necessary for the execution of
VEGF-induced proliferation, migration, and tube formation of cultured
endothelial cells in vitro and the onset of angiogenesis on tumors in vivo.
Ellagic acid is a naturally existing small molecular polyphenol widely found
in fruits and vegetables. It was reported that ellagic aicd interfered with some
angiogenesis-dependent pathologies. Yet the mechanisms involved were not
fully understood.
Thus we analyzed its anti-angiogenesis effects and mechanisms on human
breast cancer utilizing in vitro and in vivo methodologies. Besides, the in
silico analysis was carried out to further analyze the structure-based
interaction between ellagic aicd and VEGFR-2. The influences of ellagic aicd
on VEGF-induced endothelial cells were studied by proliferation, tube
formation and migration in vitro experiments. Kinase activity assay and
western blotting were utilized to explore the effects of ellagic aicd on
VEGFR-2 induced signaling pathway. Organ-based chick aortic ring model, in
vivo Chorioallantoic membrane model and in vivo breast cancer xenografts
were built to determine the anti-angiogenesis effects of ellagic aicd. Besides,
software LigandFit algorithm in Discovery Studio 2.1 (Accelrys Inc., San
Diego, CA) was applied to further understand the structure-based interaction
between ellagic aicd and VEGFR-2.
We found that ellagic aicd impeded a series of VEGF-induced angiogenesis
processes including proliferation, migration and tube formation of endothelial
cells. Besides, it directly inhibited VEGFR-2 tyrosine kinase activity and its
downstream signaling pathways including MAPK and PI3K/Akt on
endothelial cells. Ellagic aicd also obviously inhibited sprouts formation from
chicken aorta and neo-vessel formation in chick chorioallantoic membrane.
The growth and the P-VEGFR2 expression in breast tumors treated with
ellagic aicd were also significantly suppressed. In the molecular docking
simulation experiment, the structure-based interaction of VEGFR-2 with
ellagic acid was found to be stable conformation by hydrogen bonds within
residues Lys866 and Glu883 as well as by π–π interactions within residue
Phe1045 at ATP binding pocket of VEGFR-2 catalytic domain. Taken together,
ellagic aicd could exert anti-angiogenesis effects via VEGFR-2 signaling
pathway in breast cancer. / published_or_final_version / Chinese Medicine / Master / Master of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/181909 |
| Date | January 2012 |
| Creators | Wang, Neng, 王能 |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47869331 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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