title: WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-angiogenic activities via Src-homology-2-domain-containing protein tyrosine phosphatase 1.
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.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan.
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Chang
authors.affiliation: Division of General Surgery, Department of Surgery, Landseed Hospital, Taoyuan, Taiwan.
authors.forename: Ya-Fen
authors.initials: YF
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Pei-Ting
authors.initials: PT
authors.lastname: Chiu
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shiu-Wen
authors.initials: SW
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Ou
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D009281:Naphthalenes / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin
chemical_list: D020533:Angiogenesis Inhibitors; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D009281:Naphthalenes; D000077022:Survivin; C000600248:WMJ-S-001; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases