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 responses.
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.
Keywords: Angiogenesis, ellagic acid, hamster buccal pouch, histone deacetylases, protein kinases, vascular endothelial growth factor.
What Makes Species Productive of Anti-Cancer Drugs? Clues from Drugs’ Species Origin, Druglikeness, Target and Pathway
Anti-Cancer Agents in Medicinal Chemistry Roles of Epithelial-Mesenchymal Transition in Cancer Drug Resistance
Current Cancer Drug Targets Synthesis, Preferentially Hypoxic Apoptosis and Anti-Angiogenic Activity of 3- Amino-1,2,4-Benzotriazine-1,4-Dioxide Bearing Alkyl Linkers with a 3-Amino-1,2,4- Benzotriazine-1-Oxide Moiety
Anti-Cancer Agents in Medicinal Chemistry The Preclinical Bases of the Rational Combination of Paclitaxel and Antiangiogenic Drugs
Clinical Cancer Drugs Small Molecules and Alzheimer’s Disease: Misfolding, Metabolism and Imaging
Current Alzheimer Research Overexpression of Nemo-like Kinase Promotes the Proliferation and Invasion of Lung Cancer Cells and Indicates Poor Prognosis
Current Cancer Drug Targets Transposable Elements in Cancer and Other Human Diseases
Current Cancer Drug Targets Structure-Based Design of Novel Anti-Cancer Agents TargetingAurora Kinases
Current Medicinal Chemistry - Anti-Cancer Agents Air Pollution and Lung Cancer
Current Respiratory Medicine Reviews Magnetic Resonance Imaging of the Cervix, and its Relevance to the Revised International Federation of Gynecology and Obstetrics (FIGO) Staging
Current Medical Imaging Delivery of Peptidic Gonadotropin Releasing Hormone Antagonists
Current Drug Delivery Runx1/AML1 is a Guardian of Hematopoietic Stem Cells
Current Cancer Therapy Reviews Novel N-mustard-benzimidazoles/benzothiazoles Hybrids, Synthesis and Anticancer Evaluation
Anti-Cancer Agents in Medicinal Chemistry Cancer Immunoinformatics: A Promising Era in the Development of Peptide Vaccines for Human Papillomavirus-induced Cervical Cancer
Current Pharmaceutical Design Transferrin-Conjugated Nanocarriers as Active-Targeted Drug Delivery Platforms for Cancer Therapy
Current Pharmaceutical Design The Typical Metabolic Modifiers Conferring Improvement in Cancer Resistance
Current Medicinal Chemistry A New Class of Pure Estrogen Alpha Receptor Antagonists; Design, Synthesis and in-vitro Screening
Letters in Drug Design & Discovery Glycosylation Pathways as Drug Targets for Cancer: Glycosidase Inhibitors
Mini-Reviews in Medicinal Chemistry Evaluation of A Novel GLP-1R Ligand for PET Imaging of Prostate Cancer
Anti-Cancer Agents in Medicinal Chemistry MRI Evaluation of Treatment Response for Local Therapies for Malignant Liver Lesions
Current Cancer Therapy Reviews