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Title
  • A small oxazine compound as an anti-tumor agent : A novel pyranoside mimetic that binds to VEGF, HB-EGF, and TNF-α
Creator

Basappa

Murugan, Sengottuvelan

Kavitha, Chandagirikoppal V.

Purushothaman, Anurag

Nevin, Kottayath G.

Sugahara, Kazuyuki

NRID 1000060154449

Rangappa, Kanchugarakoppal S.

Subject
  • Other Pyranoside mimetic
  • Other Anti-tumor
  • Other Metastasis
  • Other Growth factor
  • Other Heparanase
  • NDC 493
Description
Other
  • A novel pyranoside mimetic compound, DMBO (2-(2,6-difluorophenyl)-4a,5,6,7,8,8a-hexahydro-4a-(4-methoxyphenyl)-4H-benzo[e][1,3]oxazine), was designed and synthesized. The sugar mimicking behavior of DMBO was addressed by its ability to bind several cytokines/growth factors such as tumor necrosis factor (TNF)-α, heparin-binding epidermal growth factor-like growth factor (HB-EGF) and vascular endothelial growth factor (VEGF) involved in cancer progression as detected through novel surface plasmon resonance imaging. In addition, DMBO inhibited the binding of TNF-α to anti-TNF-α antibody in vitro and also the production of TNF-α in vivo. The effect of DMBO on TNF-α was supported by our finding that it inhibited the proliferation of metastatic human ovarian cancer cell line (OVSAHO), which abundantly express TNF-α. High-throughput screening of DMBO showed a significant inhibition of heparanase activity at higher concentrations in vitro. DMBO also affected the heparan-degrading activity of mouse osteosarcoma cell line (LM8G7) in a dose-dependent manner, and showed a prominent inhibitory effect on the metastasis of LM8G7 cells to mouse liver. These responses are associated with the strong inhibition of migration, adhesion, invasion and proliferation of LM8G7 cells and also with the anti-angiogenic activity of DMBO. In addition, DMBO markedly inhibited the ectopic secretion of VEGF by LM8G7 cells, which drives the metastatic potential of LM8G7. Furthermore, the interaction of DMBO with HB-EGF was significantly correlated with inhibition of the proliferation of human ovarian cancer cell line (SKOV-3). These results emphasize that DMBO mimics heparan sulfate structurally and its anti-metastatic activity is likely expressed through binding to multiple factors, which are critical for tumor development and progression.
PublisherElsevier Ireland
Date Issued 2010-11-28
Languageeng
NIItypejournal article
VersiontypeAM
Identifier URI http://hdl.handle.net/2115/49204
Relation
  • isIdenticalTo PMID 20831981
  • isIdenticalTo DOI https://doi.org/10.1016/j.canlet.2010.05.016
Journal
    • ISSN 0304-3835
    • Cancer Letters
    297(2), 231-243
File
Oaidate2019-03-15T05:20:35Z