Antiangiogenic mechanisms of PJ-8, a novel inhibitor of vascular endothelial growth factor receptor signaling

Shiu Wen Huang, Jin Cherng Lien, Sheng Chu Kuo, Tur Fu Huang

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Angiogenesis occurs not only during tissue growth and development but also during wound healing and tumor progression. Angiogenesis is a balanced process controlled by proangiogenic and antiangiogenic molecules. As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for antiangiogenic and cancer therapeutic agents. In an effort to develop novel inhibitors to block VEGF signaling, we selected Pj-8, a benzimidazole derivative, and investigated its inhibitory mechanisms in human umbilical vascular endothelial cells (HUVECs). Pj-8 concentration-dependently inhibited VEGF-induced proliferation, migration and tube formation of HUVECs. Pj-8 also suppressed VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization of implanted matrigel plugs in vivo. Pj-8 inhibited VEGF-induced phosphorylation of VEGF receptor (VEGFR) 2 and the downstream protein kinases, including Akt, focal adhesion kinase, extracellular signal-regulated kinases and Src. Results from in vitro kinase assay further demonstrated that Pj-8 suppressed the kinase activity of 3-phosphoinositide-dependent kinase 1 (PDK1). Using xenograft tumor angiogenesis model, Pj-8 markedly eliminated tumor-associated angiogenesis. Taken together, our findings suggest that Pj-8 inhibits VEGF and tumor cells MDA-MB-231-induced angiogenesis, and it may be a potential drug candidate in anticancer therapy. Downregulation of VEGFR2-mediated signaling may contribute to its antiangiogenic actions.

Original languageEnglish
Pages (from-to)1022-1030
Number of pages9
JournalCarcinogenesis
Volume33
Issue number5
DOIs
Publication statusPublished - May 7 2012
Externally publishedYes

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Vascular Endothelial Growth Factor Receptor
Vascular Endothelial Growth Factor A
Umbilicus
Neoplasms
3-Phosphoinositide-Dependent Protein Kinases
Phosphotransferases
Endothelial Cells
Vascular Endothelial Growth Factor Receptor-2
Focal Adhesion Protein-Tyrosine Kinases
Extracellular Signal-Regulated MAP Kinases
Microvessels
Growth and Development
Heterografts
Wound Healing
Protein Kinases
Down-Regulation
Phosphorylation
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research

Cite this

Antiangiogenic mechanisms of PJ-8, a novel inhibitor of vascular endothelial growth factor receptor signaling. / Huang, Shiu Wen; Lien, Jin Cherng; Kuo, Sheng Chu; Huang, Tur Fu.

In: Carcinogenesis, Vol. 33, No. 5, 07.05.2012, p. 1022-1030.

Research output: Contribution to journalArticle

Huang, Shiu Wen ; Lien, Jin Cherng ; Kuo, Sheng Chu ; Huang, Tur Fu. / Antiangiogenic mechanisms of PJ-8, a novel inhibitor of vascular endothelial growth factor receptor signaling. In: Carcinogenesis. 2012 ; Vol. 33, No. 5. pp. 1022-1030.
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