title: A small oxazine compound as an anti-tumor agent: a novel pyranoside mimetic that binds to VEGF, HB-EGF, and TNF-α.
abstract: 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)-α 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-α 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 modelofosteosarcoma. These preclinical data shows the potential anti-cancer effects of DMBO.
authors.affiliation: Laboratory of Proteoglycan Signaling and Therapeutics, Faculty of Advanced Life Science, Hokkaido University Graduate School of Life Science, Sapporo, Japan.
authors.lastname: Basappa
authors.forename: Sengottuvelan
authors.initials: S
authors.lastname: Murugan
authors.forename: Chandagirikoppal V
authors.initials: CV
authors.lastname: Kavitha
authors.forename: Anurag
authors.initials: A
authors.lastname: Purushothaman
authors.forename: Kottayath G
authors.initials: KG
authors.lastname: Nevin
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D005966:Glucuronidase / Q000037:antagonists & inhibitors; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D020533:Angiogenesis Inhibitors; D048588:Benzoxazines; D005966:Glucuronidase; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D042442:Vascular Endothelial Growth Factors; D000099175:Heparanase; C552817:2-(2,6-difluorophenyl)-4a,5,6,7,8,8a-hexahydro-4a-(4-methoxyphenyl)-4H-benzo(e)(1,3)oxazine; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse