Abstract
Angiogenesis is a key step for tumour growth and metastasis, and anti-angiogenesis has been proposed as an important strategy for cancer therapy. Tryptanthrin is a weakly basic alkaloid isolated from the dried roots of medicinal indigo plants and has been shown to possess anti-tumour activities on various cancer cell types. This study aims to investigate the in vitro and in vivo anti-angiogenic activities of tryptanthrin and to unravel its underlying molecular action mechanisms. Our results show that tryptanthrin inhibited the in vitro proliferation, migration, and tube formation of the human microvascular endothelial cells (HMEC-1) in a concentration-dependent manner and significantly suppressed angiogenesis in Matrigel plugs in mice. Mechanistic studies indicated that tryptanthrin reduced the expression of several pro-angiogenic factors (Ang-1, PDGFB and MMP2). Tryptanthrin was also found to suppress the VEGFR2-mediated ERK1/2 signalling pathway in HMEC-1 cells and molecular docking simulation indicated that tryptanthrin could bound to the ATP-binding site of VEGFR2. Collectively, the present study demonstrated that tryptanthrin exhibited both in vitro and in vivo anti-angiogenic activities by targeting the VEGFR2-mediated ERK1/2 signalling pathway and might have therapeutic potential for the treatment of angiogenesis-related diseases.
Highlights
Angiogenesis, the formation of new blood vessels from preexisting vascular network, plays an important role in the tumour growth, invasion and metastasis [1,2]
Tryptanthrin Suppressed Migration and Tube Formation of Human Microvascular Endothelial Cells Endothelial cell migration and tube formation are early events and necessary steps involved in tumour angiogenesis [32,33]
These results suggested that tryptanthrin could inhibit angiogenesis in vitro
Summary
Angiogenesis, the formation of new blood vessels from preexisting vascular network, plays an important role in the tumour growth, invasion and metastasis [1,2]. Vascular endothelial growth factor receptor 2 (VEGFR2) is the primary receptor of VEGF and the major mediator of VEGF-induced proangiogenesis signalling in endothelial cells [6,7]. Tumour angiogenesis is an important control point in the progression of cancer and its inhibition is emerging as a potentially valuable new approach to cancer therapy [1,7,13]. Multiple tyrosine kinase inhibitors of VEGFR and other growth factor receptors, such as Sunitinib and Sorafenib, have been successfully used in the clinic to treat renal carcinoma [13,16]
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