Oncotarget

Research Papers:

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

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

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Oncotarget. 2015; 6:85-100. https://doi.org/10.18632/oncotarget.2765

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Abstract

Yi-Fang Chang1,2, Ya-Fen Hsu3, Pei-Ting Chiu4, Wei-Jan Huang5, Shiu-Wen Huang6, George Ou7, Joen-Rong Sheu1,4,8 and Ming-Jen Hsu4,8

1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

2 Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan

3 Division of General Surgery, Department of Surgery, Landseed Hospital, Taoyuan, Taiwan

4 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan

5 Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan

6 Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

7 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

8 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Correspondence:

Joen-Rong Sheu, email:

Ming-Jen Hsu, email:

Keywords: Angiogenesis; Endothelial cells; Hydroxamate; p53; VEGF

Received: August 04, 2014 Accepted: November 15, 2014 Published: November 16, 2014

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.


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