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The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF‐κB pathway
Author(s) -
Watari Kosuke,
Nakamura Mamiyo,
Fukunaga Yuichi,
Furuno Ayana,
Shibata Tomohiro,
Kawahara Akihiko,
Hosoi Fumihito,
Kuwano Takashi,
Kuwano Michihiko,
Ono Mayumi
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26356
Subject(s) - angiogenesis , vascular endothelial growth factor , cancer research , protein kinase b , vascular endothelial growth inhibitor , biology , angiogenesis inhibitor , vascular endothelial growth factor a , kinase insert domain receptor , tumor necrosis factor alpha , mapk/erk pathway , signal transduction , microbiology and biotechnology , chemistry , immunology , vegf receptors
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.