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