Abstract | BACKGROUND: Anti-angiogenesis targeting VEGFR2 has been considered as an important strategy for cancer therapy. Tylophorine is known to possess anti-inflammatory and antitumor activity, but its roles in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is still unknown. Therefore, we examined its anti-angiogenic effects and mechanisms in vitro and in vivo. METHODS: We used tylophorine and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro and Ehrlich ascites carcinoma (EAC) tumor in vivo. RESULTS:
Tylophorine significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR2 tyrosine kinase activity and its downstream signaling pathways including Akt, Erk and ROS in endothelial cells. Using HUVECs we demonstrated that tylophorine inhibited VEGF-stimulated inflammatory responses including IL-6, IL-8, TNF-α, IFN-γ, MMP-2 and NO secretion. Tylophorine significantly inhibited neovascularization in sponge implant angiogenesis assay and also inhibited tumor angiogenesis and tumor growth in vivo. Molecular docking simulation indicated that tylophorine could form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit. CONCLUSION:
|
Authors | Sarita Saraswati, Pawan K Kanaujia, Shakti Kumar, Ranjeet Kumar, Abdulqader A Alhaider |
Journal | Molecular cancer
(Mol Cancer)
Vol. 12
Pg. 82
(Jul 29 2013)
ISSN: 1476-4598 [Electronic] England |
PMID | 23895055
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Alkaloids
- Angiogenesis Inhibitors
- Antineoplastic Agents, Phytogenic
- Cytokines
- Indolizines
- Phenanthrenes
- Vascular Endothelial Growth Factor A
- Nitric Oxide
- Vascular Endothelial Growth Factor Receptor-2
- Matrix Metalloproteinase 2
- tylophorine
|
Topics |
- Alkaloids
(administration & dosage, chemistry, pharmacology)
- Angiogenesis Inhibitors
(administration & dosage, chemistry, pharmacology)
- Animals
- Antineoplastic Agents, Phytogenic
(administration & dosage, chemistry, pharmacology)
- Cell Movement
(drug effects)
- Cell Proliferation
(drug effects)
- Cell Survival
(drug effects)
- Cytokines
(metabolism)
- Disease Models, Animal
- Female
- Human Umbilical Vein Endothelial Cells
(drug effects, metabolism)
- Humans
- Indolizines
(administration & dosage, chemistry, pharmacology)
- Male
- Matrix Metalloproteinase 2
(metabolism)
- Mice
- Molecular Conformation
- Molecular Docking Simulation
- Neoplasms
(drug therapy, metabolism, mortality, pathology)
- Neovascularization, Physiologic
(drug effects)
- Nitric Oxide
(metabolism)
- Phenanthrenes
(administration & dosage, chemistry, pharmacology)
- Protein Binding
(drug effects)
- Protein Interaction Domains and Motifs
- Signal Transduction
(drug effects)
- Tumor Burden
(drug effects)
- Tylophora
(chemistry)
- Vascular Endothelial Growth Factor A
(metabolism)
- Vascular Endothelial Growth Factor Receptor-2
(antagonists & inhibitors, chemistry, metabolism)
- Xenograft Model Antitumor Assays
|