title: MART-10, the new brand of 1α,25(OH)2D3 analog, is a potent anti-angiogenic agent in vivo and in vitro.
abstract: BACKGROUND
  Angiogenesis is the hall marker for cancer growth and metastasis. Thus, anti-angiogenesis emerges as a new way to treat cancer. 1α,25(OH)2D3 is recently getting popular due to the non-mineral functions, which have been applied fore cancer treatment. The newly-synthesized 1α,25(OH)2D3 analog, MART-10, has been proved to be much more potent than 1α,25(OH)2D3 regarding inhibiting cancer cells growth and metastasis without inducing hypercalcemia in vivo. In this study, we aimed to investigate the effect of MART-10 and 1α,25(OH)2D3 on angiogenesis in vitro and in vivo.
  
  
  RESULTS
  MART-10 and 1α,25(OH)2D3 were able to repress VEGFA-induced human umbilical vein endothelial cells (HUVECs) migration, invasion and tube formation, but not proliferation, with MART-10 much more potent than 1α,25(OH)2D3. The Chick Chorioallantoic Membrane (CAM) assay and matrigeal angiogenesis assay further confirmed the in vivo more potent anti-angiogenesis effect of MART-10. MART-10 inhibited the VEGFA-induced HUVECs angiogenesis process through downregulation of Akt and Erk 1/2 phosphorylation. The VEGFA-VEGFR2 (VEGF receptor 2) axis is the main signal transducing pathway to stimulate angiogenesis. A positive autocrine manner was found for the first time in HUVECs as treated by VEGFA, which induced VEGFA expression and secretion, and VEGFR2 expression. MART-10 and 1α,25(OH)2D3 were demonstrated to be able to repress this positive autocrine manner, thus inhibiting angiogenesis.
  
  
  CONCLUSIONS
  MART-10 and 1α,25(OH)2D3 both are effective anti-angiogenesis agents. Given MART-10 is much more potent than 1α,25(OH)2D3 and active in vivo without obvious side effect, MART-10 should be deemed as a promising anti-cancer agent.
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.affiliation: Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC.
authors.forename: Chi-Chin
authors.initials: CC
authors.lastname: Sun
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, and Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Ming-Huang
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, Institute of Biopharmaceutical Sciences, and Genome Research Center, Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Chi-Ying
authors.initials: CY
authors.lastname: Huang
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Kwei-Shan, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Jun-Te
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Kwei-Shan, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Department of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, ROC.
authors.forename: Sheng-Fong
authors.initials: SF
authors.lastname: Kuo
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan Taoyuan 333, Taiwan, ROC.
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa, 252-5195, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa, 252-5195, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.affiliation: Boston University School of Medicine, M-1022, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Kwei-Shan, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, ROC.
authors.forename: Jong-Hwei S
authors.initials: JH
authors.lastname: Pang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology; D049033:Chorioallantoic Membrane / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D008807:Mice, Inbred BALB C; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C569618:19-nor-2-(3-hydroxypropyl)-1,25-dihydroxyvitamin D3; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D002762:Cholecalciferol; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: 1α,25(OH)(2)D(3); Angiogenesis; HUVEC; MART-10; Vitamin D