Tylophorine, a phenanthraindolizidine alkaloid isolated from Tylophora indica exerts antiangiogenic and antitumor activity by targeting vascular endothelial growth factor receptor 2–mediated angiogenesis

Abstract

BackgroundAnti-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.MethodsWe used tylophorine and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro and Ehrlich ascites carcinoma (EAC) tumor in vivo.ResultsTylophorine 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.ConclusionTylophorine exerts anti-angiogenesis effects via VEGFR2 signaling pathway thus, may be a viable drug candidate in anti-angiogenesis and anti-cancer therapies.

Different 4T1 Cells Migration under Caesalpinia sappan L. and Ficus septica Burm.f Ethanolic Extracts

“…In our experiment, EFS looked better in inhibiring cells migration than ECS. This phenomenon possibly occured due to its different active compound such as Brazilein and Brazilin (phenolic compounds) in C. sappan and tylophorine (alkaloid) in F. septica Burm.f Tylophorine, isolated from Tylophora indica, was revealed could inhibit angiogenesis via vascular endhotelial growth factor receptor 2 (VEGFR2) signaling pathway (Saraswati, et al, 2013). Our data give insign for further investigation to gain the detail information about this effect.…”

Marine Sponge Derived Antiangiogenic Compounds

“…Molecular docking simulation indicated that tylophorine could interact with the ATP-binding sites of VEGFR2 kinase domain. All these data indicate that tylophorine exerts potent anti-angiogenesis activities via specifically targeting VEGFR2 and its signaling pathway, suggesting that it could be a promising candidate for development of anti-angiogenesis agents [89].…”

PubChem applications in drug discovery: a bibliometric analysis

“…PubChem structures were also downloaded for characterizing ligand–protein interaction through docking, molecular dynamics (MD) simulation, binding energy calculation or other molecular modeling techniques [39–41]. Such studies were often performed after the identification of lead compounds by experimental chemists and pharmacologists aiming to investigate specific compound–target interactions that could benefit further drug optimization or de novo drug design.…”