WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-angiogenic activities via Src-homology-2-domaincontaining protein tyrosine phosphatase 1

Yi Fang Chang, Ya Fen Hsu, Pei Ting Chiu, Wei Jan Huang, Shiu Wen Huang, George Ou, Joen Rong Sheu, Ming Jen Hsu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Angiogenesis, one of the major routes for tumor invasion and metastasis represents a rational target for therapeutic intervention. Recent development in drug discovery has highlighted the diverse biological and pharmacological properties of hydroxamate derivatives. In this study, we characterized the anti-angiogenic activities of a novel aliphatic hydroxamate, WMJ-S-001, in an effort to develop novel angiogenesis inhibitors. WMJ-S-001 inhibited vascular endothelial growth factor (VEGF)-A-induced proliferation, invasion and endothelial tube formation of human umbilical endothelial cells (HUVECs). WMJ-S-001 suppressed VEGF-A-induced microvessel sprouting from aortic rings, and attenuated angiogenesis in in vivo mouse xenograft models. In addition, WMJ-S-001 inhibited the phosphorylations of VEGFR2, Src, FAK, Akt and ERK in VEGF-A-stimulated HUVECs. WMJ-S-001 caused an increase in SHP-1 phosphatase activity, whereas NSC-87877, a SHP-1 inhibitor, restored WMJ-S-001 suppression of VEGFR2 phosphorylation and cell proliferation. Furthermore, WMJ-S-001 inhibited cell cycle progression and induced cell apoptosis in HUVECs. These results are associated with p53 phosphorylation and acetylation and the modulation of p21 and survivin. Taken together, WMJ-S-001 was shown to modulate vascular endothelial cell remodeling through inhibiting VEGFR2 signaling and induction of apoptosis. These results also support the role of WMJ-S-001 as a potential drug candidate and warrant the clinical development in the treatment of cancer.

Original languageEnglish
Pages (from-to)85-100
Number of pages16
JournalOncotarget
Volume6
Issue number1
Publication statusPublished - 2015

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Keywords

  • Angiogenesis
  • Endothelial cells
  • Hydroxamate
  • p53
  • VEGF

ASJC Scopus subject areas

  • Oncology

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