Tryptanthrin Inhibits Angiogenesis by Targeting the VEGFR2-Mediated ERK1/2 Signalling Pathway

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.

Benzo[b]tryptanthrin Inhibits MDR1, Topoisomerase Activity, and Reverses Adriamycin Resistance in Breast Cancer Cells

“…Chemistry Benzo [5,6]indolo[2,1-b]quinazoline-6,14-dione (benzo[b]tryptanthrin) was prepared as previously published.…”

“…[4,5] A plethora of biological and pharmacological activities of tryptanthrin have been reported; tryptanthrin suppressed angiogenesis in a Matrigel plug assay in vivo by reducing the expression of angiogenic factors such as Ang-1, PDGFB, and MMP2, as well as VEGFR2-mediated ERK1/2 signals. [6] Tryptanthrin ameliorated clinical symptoms and skin lesions of apoptotic dermatitis induced by 2,4-dinitrofluorobenzene through down-regulation of thymic stromal lymphopoietin. [7] Tryptanthrin also showed antitumoral activity by targeting indoleamine 2,3-dioxygenase (IDO-1), and 8-fluorotryptanthrin, a stronger IDO-1 inhibitor than tryptanthrin, potently suppressed tumor growth in Lewis lung cancer tumor-bearing mice.…”

Quercetin and Tryptanthrin

“…Neuroblastoma, an extracranial cancer that occurs most commonly in children, Inhibition of growth and colony forming ability Cellular differentiation Cell cycle arrest N-myc [103] shows amplification of N-myc in its advanced stages. Any agent that can stimulate differentiation of neuroblastoma cells and downregulate N-myc can inhibit their proliferation.…”

“…Liao et al have reported that tryptanthrin has the ability to inhibit angiogenesis, one of the key steps in tumor growth and metastasis by targeting the VEGFR2-mediated ERK1/2 signaling pathway both in in vitro and in vivo conditions [103].…”

Fully human VEGFR2 monoclonal antibody BC001 attenuates tumor angiogenesis and inhibits tumor growth

“…With a general interest in dissecting VEGFR2 signaling, a growing number of evidence demonstrates that VEGFR2 is predominantly responsible for responses of vascular endothelial cells to VEGF under both physiological and pathological conditions, and plays important role in the process of angiogenesis through affecting vascular permeability, proliferation, survival and migration (9,10). However, as a therapeutic target, the attractiveness of VEGFR2 is multifaceted.…”