RRC ID 18635
Author Watari K, Nakamura M, Fukunaga Y, Furuno A, Shibata T, Kawahara A, Hosoi F, Kuwano T, Kuwano M, Ono M.
Title The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-κB pathway.
Journal Int. J. Cancer
Abstract Development of a novel type of angiogenesis inhibitor will be essential for further improvement of therapeutics against cancer patients. We examined whether an octahydronaphthalene derivative, AMF-26, which was screened as an inhibitor of intercellular adhesion molecule-1 (ICAM-1) production stimulated by inflammatory stimuli in vascular endothelial cells, could block angiogenesis in response to vascular endothelial growth factor (VEGF) and/or inflammatory cytokines. Low dose AMF-26 effectively inhibited the tumor necrosis factor-α (TNF-α)- or the interleukin-1β (IL-1β)-induced production of ICAM-1 in human umbilical vascular endothelial cells (HUVECs). We found that the TNF-α-induced phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear translocation of p65 were impaired by AMF-26 in both endothelial cells and cancer cells. AMF-26 was found to inhibit the phosphorylation of VEGF receptor 1 (VEGFR1), VEGFR2 and the downstream signaling molecules Akt, extracellular signal-regulated kinase (ERK)1/2 stimulated by VEGF in HUVECs. Therefore, the VEGF-induced proliferation, migration and tube formation of vascular endothelial cells was highly susceptible to inhibition by AMF-26. Oral administration of AMF-26 significantly blocked VEGF- or IL-1β-induced angiogenesis in the mouse cornea, and also tumor angiogenesis and growth. Together, our results indicate that AMF-26 inhibits angiogenesis through suppression of both VEGFR1/2 and nuclear factor-κB (NF-κB) signaling pathways when stimulated by VEGF or inflammatory cytokines. AMF-26 could be a promising novel candidate drug for cancer treatments.
Volume 131(2)
Pages 310-21
Published 2012-7-15
DOI 10.1002/ijc.26356
PMID 21826646
MeSH Angiogenesis Inhibitors / pharmacology* Animals Cell Line Cell Movement Cell Proliferation Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors Extracellular Signal-Regulated MAP Kinases / metabolism Human Umbilical Vein Endothelial Cells Humans I-kappa B Proteins / metabolism Intercellular Adhesion Molecule-1 / biosynthesis Interleukin-1beta / antagonists & inhibitors Male Mice Mice, Inbred BALB C Mice, Inbred C57BL NF-KappaB Inhibitor alpha NF-kappa B / metabolism* Naphthols / pharmacology* Neovascularization, Physiologic / drug effects* Neovascularization, Physiologic / physiology Oncogene Protein v-akt / metabolism Phosphorylation Pyridines / pharmacology* Receptors, Vascular Endothelial Growth Factor / metabolism* Signal Transduction / drug effects Transcription Factor RelA / antagonists & inhibitors Tumor Necrosis Factor-alpha / antagonists & inhibitors
IF 7.36
Times Cited 9
Human and Animal Cells B16/BL6 (RCB2638)