title: Tylophorine, a phenanthraindolizidine alkaloid isolated from Tylophora indica exerts antiangiogenic and antitumor activity by targeting vascular endothelial growth factor receptor 2-mediated angiogenesis.
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.
  
  
  CONCLUSIONS
  Tylophorine exerts anti-angiogenesis effects via VEGFR2 signaling pathway thus, may be a viable drug candidate in anti-angiogenesis and anti-cancer therapies.
authors.affiliation: Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia. saritasaraswati@gmail.com
authors.forename: Sarita
authors.initials: S
authors.lastname: Saraswati
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Kanaujia
authors.forename: Shakti
authors.initials: S
authors.lastname: Kumar
authors.forename: Ranjeet
authors.initials: R
authors.lastname: Kumar
authors.forename: Abdulqader A
authors.initials: AA
authors.lastname: Alhaider
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007212:Indolizines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D010616:Phenanthrenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D031110:Tylophora / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000470:Alkaloids; D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D007212:Indolizines; D010616:Phenanthrenes; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D040301:Vascular Endothelial Growth Factor Receptor-2; D020778:Matrix Metalloproteinase 2; C004218:tylophorine
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