A natural anti-inflammatory enone fatty acid inhibits angiogenesis by attenuating nuclear factor-κB signaling in vascular endothelial cells.
An anti-inflammatory enone fatty acid, (E)-9-oxooctadec-10-enoic acid (C10), was previously isolated from red alga (Gracilaria verrucosa). Of the many cellular signaling pathways activated in response to the inflammatory stimulus, lipopolysaccharide, the extracellular signal-regulated kinase 1/2, the stress-activated protein kinase/Jun N-terminal kinase and the nuclear factor-κB pathways were specifically blocked by C10 in the macrophage-like cell line, RAW264.7. In this study, we investigated the anti-angiogenic and anti-inflammatory activities of C10 in endothelial cells. C10 only partially inhibited the proliferation of human cancer cell lines at relatively high concentrations of over 20 μg/ml. However, C10 inhibited the proliferation of RAW264.7 cells and human umbilical vein endothelial cells (HUVECs) with half-maximal inhibitory concentration (IC50) values of 4-8 μg/ml. Both the proliferation and the migration of HUVECs induced by the vascular endothelial growth factor (VEGF) were markedly blocked by C10 with IC50 values of 2-3 μg/ml. The activation of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α, by tumor necrosis factor-α or VEGF in these cells was also blocked by C10. Furthermore, in an in vivo model of angiogenesis in the mouse cornea, the neovascularization induced by VEGF was markedly inhibited by C10. The processes involved in inflammatory signaling, angiogenesis, and the development of malignancy in cancer are closely related, suggesting that C10 could be a useful lead compound for the development of novel anti-angiogenic therapies for cancer.
Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
Ayana
A
Furuno
Kosuke
K
Watari
Mamiyo
M
Nakamura
Yuichi
Y
Fukunaga
Jee H
JH
Jung
Mayumi
M
Ono
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D005227:Fatty Acids; D047028:Macrocyclic Compounds; D016328:NF-kappa B; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A