The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-κB pathway

Kosuke Watari, Mamiyo Nakamura, Yuichi Fukunaga, Ayana Furuno, Tomohiro Shibata, Akihiko Kawahara, Fumihito Hosoi, Takashi Kuwano, Michihiko Kuwano, Mayumi Ono

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)310-321
Number of pages12
JournalInternational Journal of Cancer
Volume131
Issue number2
DOIs
Publication statusPublished - Jul 15 2012

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Vascular Endothelial Growth Factor Receptor
Angiogenesis Inhibitors
Endothelial Cells
Vascular Endothelial Growth Factor A
Umbilicus
Intercellular Adhesion Molecule-1
Interleukin-1
Neoplasms
Tumor Necrosis Factor-alpha
Phosphorylation
Cytokines
Vascular Endothelial Growth Factor Receptor-1
Mitogen-Activated Protein Kinase 3
N-(pyridine-3-ylmethyl)-5-(7-hydroxy-2,6,8-trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-yl)-2-methylpenta-2,4-dienamide
Mitogen-Activated Protein Kinase 1
Cornea
Oral Administration
B-Lymphocytes
Light
Peptides

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-κB pathway. / Watari, Kosuke; Nakamura, Mamiyo; Fukunaga, Yuichi; Furuno, Ayana; Shibata, Tomohiro; Kawahara, Akihiko; Hosoi, Fumihito; Kuwano, Takashi; Kuwano, Michihiko; Ono, Mayumi.

In: International Journal of Cancer, Vol. 131, No. 2, 15.07.2012, p. 310-321.

Research output: Contribution to journalArticle

Watari, K, Nakamura, M, Fukunaga, Y, Furuno, A, Shibata, T, Kawahara, A, Hosoi, F, Kuwano, T, Kuwano, M & Ono, M 2012, 'The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-κB pathway', International Journal of Cancer, vol. 131, no. 2, pp. 310-321. https://doi.org/10.1002/ijc.26356
Watari, Kosuke ; Nakamura, Mamiyo ; Fukunaga, Yuichi ; Furuno, Ayana ; Shibata, Tomohiro ; Kawahara, Akihiko ; Hosoi, Fumihito ; Kuwano, Takashi ; Kuwano, Michihiko ; Ono, Mayumi. / The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-κB pathway. In: International Journal of Cancer. 2012 ; Vol. 131, No. 2. pp. 310-321.
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