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

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.

• Authors: Kosuke Watari, Mamiyo Nakamura, Yuichi Fukunaga, Ayana Furuno, Tomohiro Shibata, Akihiko Kawahara, Fumihito Hosoi, Takashi Kuwano, Michihiko Kuwano, Mayumi Ono
• Journal: International journal of cancer (Int J Cancer) Vol. 131 Issue 2 Pg. 310-21 (Jul 15 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 21826646 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 UICC.

Chemical References

• Angiogenesis Inhibitors
• I-kappa B Proteins
• Interleukin-1beta
• 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
• NF-kappa B
• NFKBIA protein, human
• Naphthols
• Nfkbia protein, mouse
• Pyridines
• Rela protein, mouse
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• NF-KappaB Inhibitor alpha
• Receptors, Vascular Endothelial Growth Factor
• Oncogene Protein v-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Cell Line
• Cell Movement
• Cell Proliferation
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, 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, 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)