Indirubin inhibits tumor growth by antitumor angiogenesis via blocking VEGFR2‐mediated JAK/STAT3 signaling in endothelial cell

• Published in: International journal of cancer Vol. 129; no. 10; pp. 2502 - 2511
• Main Authors: Zhang, Xiaoli, Song, Yajuan, Wu, Yuanyuan, Dong, Yanmin, Lai, Li, Zhang, Jing, Lu, Binbin, Dai, Fujun, He, Lijun, Liu, Mingyao, Yi, Zhengfang
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.11.2011; Wiley-Blackwell
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Antibiotics, Antineoplastic - pharmacology; Biological and medical sciences; Cell Line; Cell Line, Tumor; Endothelial Cells - metabolism; Humans; indirubin; Indoles - pharmacology; JAK/STAT3; Janus Kinases - metabolism; Male; Medical sciences; Mice; Prostatic Neoplasms - blood supply; Prostatic Neoplasms - drug therapy; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; tumor angiogenesis,VEGFR2; Tumors; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Xenograft Model Antitumor Assays; Antineoplastic agent; Jak protein tyrosine kinase; VEGFR2; Endothelial cell; Malignant tumor; JAK/STAT3; Angiogenesis; Signal transduction; indirubin; Cancerology; Tumor growth; Transcription factor STAT3; tumor angiogenesis; Inhibitor; Neovascularization; Vascular endothelial growth factor receptor 2; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.25909

Tumor angiogenesis is one of the hallmarks of the development in malignant neoplasias and metastasis. Many angiogenesis inhibitors are small molecules from natural products. Indirubin, the active component of a traditional Chinese herbal medicine, Banlangen, has been shown to exhibit antitumor and anti‐inflammation effects. But its roles in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is unknown. Here, we identified that indirubin inhibited prostate tumor growth through inhibiting tumor angiogenesis. Using chick chorioallantoic membrane (CAM) assay and mouse corneal model, we found that indirubin inhibited angiogenesis in vivo. We also showed the inhibition activity of indirubin in endothelial cell migration, tube formation and cell survival in vitro. Furthermore, indirubin suppressed vascular endothelial growth factor receptor 2‐mediated Janus kinase (JAK)/STAT3 signaling pathway but had little effects on the activity of extracellular signal‐regulated kinase (ERK) and p38 mitogen‐activated protein kinase in endothelial cell. Our study provided the first evidence for antitumor angiogenesis activity of indirubin and the related molecular mechanism. Our investigations suggested that indirubin was a potential drug candidate for angiogenesis related diseases.