期刊
CANCER LETTERS
卷 297, 期 2, 页码 231-243出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2010.05.016
关键词
Tumor metastases; Heparin; Growth factors; Oxazines; Sugar mimetics
类别
资金
- Indian National Science Academy (INSA)-Japan Society for the Promotion of Science (JSPS)
- JSPS [19-07194]
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT)
A novel pyranoside mimetic compound, DMBO (2-(2,6-difluorophenyl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecane), was designed and synthesized. The sugar mimicking behavior of DMBO was addressed by its ability to bind several growth factors/cytokines such as vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor-like growth factor (HB-EGF), and tumor necrosis factor (TNF)-alpha as demonstrated by the recently developed surface plasmon resonance assay. DMBO exhibited strong anti-proliferation activity in vitro against tumor cells including a highly metastatic murine osteosarcoma cell line LM8G7 that secretes VEGF as well as two human ovarian cell lines, OVSAHO and SKOV-3, which secrete TNF-alpha and HB-EGF respectively. Furthermore, DMBO inhibited the metastatic activity to the mouse liver of LM8G7 cells injected from a lateral tail vein, and affected the heparan-degrading activity of LM8G7 cells. Here, we report that DMBO acts as a human heparanase inhibitor in vitro possibly as a substrate mimetic. DMBO also inhibited the migration and invasion of LM8G7 cells and angiogenic events such as endothelial cell proliferation, migration and capillary tube-like formation in vitro. More prominently, the administration of DMBO with heparin resulted in synergistic anti-tumor effects in mouse model of osteosarcoma. These preclinical data shows the potential anti-cancer effects of DMBO. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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