Background: Blocking vascular endothelial growth factor (VEGF) mediated tumor angiogenesis by phytochemicals has
emerged as an attractive strategy for cancer prevention and therapy.
Methods: We investigated the anti-angiogenic effects of ellagic acid in a hamster model of oral oncogenesis by examining the transcript
and protein expression of hypoxia-inducible factor-1alpha (HIF-1α), VEGF, VEGFR2, and the members of the PI3K/Akt and MAPK
signaling cascades. Molecular docking studies and cell culture experiments with the endothelial cell line ECV304 were performed to
delineate the mechanism by which ellagic acid regulates VEGF signaling.
Results: We found that ellagic acid significantly inhibits HIF-1α-induced VEGF/VEGFR2 signalling in the hamster buccal pouch by
abrogating PI3K/Akt and MAPK signaling via downregulation of PI3K, PDK-1, p-Aktser473, mTOR, p-ERK, and p-JNK. Ellagic acid was
also found to reduce the expression of histone deacetylases that could inhibit neovascularization. Analysis of the mechanism revealed that
ellagic acid inhibits hypoxia-induced angiogenesis via suppression of HDAC-6 in ECV304 cells. Furthermore, knockdown of
endogenous HDAC6 via small interfering RNA abrogated hypoxia-induced expression of HIF-1α and VEGF and blocked Akt activation.
Molecular docking studies confirmed interaction of ellagic acid with upstream kinases that regulate angiogenic signaling.
Conclusions: Taken together, these findings demonstrate that the anti-angiogenic activity of ellagic acid may be mediated by abrogation
of hypoxia driven PI3K/Akt/mTOR, MAPK and VEGF/VEGFR2 signaling pathways involving suppression of HDAC6 and HIF-1α
General Significance: Ellagic acid offers promise as a lead compound for anticancer therapeutics by virtue of its ability to inhibit key
oncogenic signaling cascades and HDACs.