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

doi:10.18632/oncotarget.2765

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.

Highlights

Angiogenesis is a complex process of forming new blood vessels from preexisting vasculature [1]
To investigate whether aliphatic hydroxamate derivatives, the WMJ-S compounds (Fig.1A), exhibit anti-angiogenic activities, BrdU labeling analysis was employed to determine the effects of WMJ-S-001, WMJ-S-002 and WMJ-S-003 on cell proliferation in vascular endothelial growth factor (VEGF)-A-stimulated Human umbilical vascular endothelial cells (HUVECs)
These results suggest that SH2 domain-containing protein tyrosine phosphatase-1 (SHP-1) is responsible for WMJ-S-001-decreased VEGFR2 phosphorylation and subsequent angiogenesis in HUVECs exposed to VEGF-A

Summary

Introduction

Angiogenesis is a complex process of forming new blood vessels from preexisting vasculature [1]. The balance between angiogenic and anti-angiogenic signaling shifts towards blood vessel formation to ensure adequate blood supply for tumor cell growth [5]. This “angiogenic switch” initiates angiogenesis which requires integrated actions of a number of angiogenic factors [6]. Activation of VEGFR2 turns on the signaling cascades including Src family kinases, Akt ( known as protein kinase B), focal adhesion kinase (FAK), and extracellular signal-regulated kinase (ERK) [16] These signaling cascades are involved in the regulation of endothelial cell proliferation, migration and survival [17,18,19]. Monoclonal antibody such as bevacizumab [26] and small molecule inhibitors such as sorafenib and sunitinib have already been approved by the United States Food and Drug Administration for treating certain tumor types [27]

Methods

Results

Conclusion