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

Molecular Cancer

Research

Shakti Kumar¹  Sarita Saraswati²  Pawan K Kanaujia³  Abdulqader A Alhaider⁴  Ranjeet Kumar⁵ 

[1] Bioinformatic Centre, North-Eastern Hill University, 793022, Shillong, India;Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia;Department of Microbiology, South Campus, University of Delhi, New Delhi, India;Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia;Laser Applications and Holography Laboratory, Instrument Design Development Centre, Indian Institute of Technology Delhi, 110016, New Delhi, India;

关键词: Tylophorine;    VEGFR2;    Antiangiogenesis;    Microvessel density;    Molecular docking;   

DOI  :  10.1186/1476-4598-12-82

 received in 2013-05-15, accepted in 2013-07-19,  发布年份 2013

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Saraswati et al.; licensee BioMed Central Ltd. 2013