Exp Mol Med.  2011 Mar;43(3):146-152. 10.3858/emm.2011.43.3.017.

5-Formylhonokiol exerts anti-angiogenesis activity via inactivating the ERK signaling pathway

• Zhu W
• Fu A
• Hu J
• Wang T
• Luo Y
• Peng M
• Ma Y
• Wei Y
• Chen L

• KMID: 1109403
• DOI: http://doi.org/10.3858/emm.2011.43.3.017

Abstract

Our previous report has demonstrated that 5-formylhonokiol (FH), a derivative of honokiol (HK), exerts more potent anti-proliferative activities than honokiol in several tumor cell lines. In present study, we first explored the antiangiogenic activities of 5-formylhonokiol on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) for the first time in vitro. Then we investigated the in vivo antiangiogenic effect of 5-formylhonokiol on zebrafish angiogenesis model. In order to clarify the underlying molecular mechanism of 5-formylhonokiol, we investigated the signaling pathway involved in controlling the angiogenesis process by western blotting assay. Wound-healing results showed that 5-formylhonokiol significantly and dose-dependently inhibited migration of cultured human umbilical vein enthothelial cells. The invasiveness of HUVEC cells was also effectively suppressed at a low concentration of 5-formylhonokiol in the transwell assay. Further F-actin imaging revealed that inhibitory effect of 5-formylhonokiol on invasion may partly contribute to the disruption of assembling stress fiber. Tube formation assay, which is associated with endothelial cells migration, further confirmed the anti-angiogenesis effect of 5-formylhonokiol. In in vivo zebrafish angiogenesis model, we found that 5-formylhonokiol dose-dependently inhibited angiogenesis. Furthermore, western blotting showed that 5-formylhonokiol significantly down-regulated extracellular signal-regulated kinase (ERK) expression and inhibited the phosphorylation of ERK but not affecting the total protein kinase B (Akt) expression and related phosphorylation, suggesting that 5-formylhonokiol might exert anti-angiogenesis capacity via down-regulation of the ERK signal pathway. Taken together, these data suggested that 5-formylhonokiol might be a viable drug candidate in antiangiogenesis and anticancer therapies.

Keyword

angiogenesis inhibitors; cell movement; cystoskeleton; extracellular signal-regulated MAP kinases; honokiol

MeSH Terms

Actins/metabolism
Angiogenesis Inhibitors/*pharmacology
Animals
Antineoplastic Agents, Phytogenic/pharmacology
Biphenyl Compounds/*pharmacology
Blotting, Western
Cell Line, Tumor
Cell Movement/drug effects
Cell Proliferation/drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drugs, Chinese Herbal
Embryo, Nonmammalian/drug effects/metabolism
Endothelium, Vascular/*drug effects/metabolism
Extracellular Signal-Regulated MAP Kinases/*antagonists & inhibitors/metabolism
Humans
Lignans/*pharmacology
Neovascularization, Physiologic/*drug effects
Signal Transduction/*drug effects
Umbilical Veins/cytology
Wound Healing
Zebrafish/embryology/metabolism