Journal
EUROPEAN JOURNAL OF CANCER
Volume 45, Issue 5, Pages 857-865Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2008.12.007
Keywords
Phosphatidylinositol 3-kinase; Angiogenesis; Inhibitor; ZSTK474
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Funding
- National Institute of Biomedical Innovation, Japan [05-13]
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [20015048]
- Japan Society for the Promotion of Science [17390032]
- Grants-in-Aid for Scientific Research [17390032, 20015048] Funding Source: KAKEN
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Angiogenesis is known to be required for tumour growth and metastasis. Recent reports indicated that phosphatidylinositol 3-kinase (PI3K) promoted angiogenesis by inducing expressions of HIF-1 alpha and vascular endothelial growth factor (VEGF). The present study aims to investigate the antiangiogenic effect of ZSTK474, a novel pan-PI3K inhibitor. ZSTK474 significantly inhibited tumour growth in the RXF-631L xenograft model. Immunohistochemical staining of the tumour tissue with anti-von Willebrand Factor antibody showed a significantly reduced number of microvessels in the ZSTK474-treated mice, suggesting the highly promising antiangiogenic activity in vivo. In human umbilical vein endothelial cells (HUVECs), submicromolar concentrations of ZSTK474 inhibited cell growth, blocked VEGF-induced cell migration and the tube formation, and thus revealed potent in vitro antiangiogenic activity. Furthermore, ZSTK474 inhibited phosphorylation of Akt at submicromolar concentrations. In RXF-631L cancer cells, on the other hand, ZSTK474 treatment inhibited the expression of HIF-1a and secretion of VEGF. Together, these results suggest that ZSTK474 has potent antiangiogenic activity, which could be attributed to dual-target inhibitory properties: inhibition of VEGF secretion by cancer cells and inhibition of PI3K in endothelial cells. (C) 2008 Elsevier Ltd. All rights reserved.
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