title: In-VitroandEx-VivoInvestigations of the Microtubule Binding Drug Targetin on Angiogenesis.
abstract: BACKGROUND
  Intervention aimed at disrupting or inhibiting newly formed vascular network is highly desired to attenuate the progression of angiogenesis-dependent diseases. In cancer, this is tightly associated with the generation of VEGF by hypoxia inducible factor-1α following its activation by hypoxia. In light of the multiple cellular roles played by microtubules and their involvement in the processing of the hypoxia inducible factor-1α transcript, modulation of microtubule dynamics is emerging as a logical approach to suppress tumor reliance on angiogenesis. Targetin is a novel noscapinoid that interferes with microtubule dynamicity and inhibits the growth of cell lines from many types of cancers.
  
  
  RESULTS
  Utilizingin-vitroandex-vivoangiogenic models, we discovered the vascular disrupting and anti-angiogenic properties of Targetin. Targetin disrupted pre-assembled capillary-like networks of human endothelial cells by severing cell-cell junctions, inhibiting endothelial cell proliferation and metabolic activity in the presence and absence of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Furthermore, we show that Targetin significantly inhibits the formation of neovasculature network sprouting from rat aortic explants stimulated with proangiogenic stimuli, namely VEGF or bFGF.
  
  
  CONCLUSIONS
  We conclude that Targetin is a potential clinically promising anti-angiogenic agent for the treatment of many diseases including cancers.
authors.affiliation: Department of Pediatrics, Laval University, Québec, Québec, G1V 4G2, Canada.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Ajeawung
authors.affiliation: Department of Pediatrics, Laval University, Québec, Québec, G1V 4G2, Canada.
authors.forename: Lotta
authors.initials: L
authors.lastname: Mononen
authors.affiliation: Department of Pediatrics, Laval University, Québec, Québec, G1V 4G2, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Thorn
authors.affiliation: Centre de recherche du CHU de Québec, Québec, G1V 4G2, Canada.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Pin
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Harish C
authors.initials: HC
authors.lastname: Joshi
authors.affiliation: Centre de recherche du CHU de Québec, Québec, G1V 4G2, Canada ; Department of Molecular Biology, Medical Biology and Pathology, Québec, Québec, G1V 4G2, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Huot
authors.affiliation: Department of Pediatrics, Laval University, Québec, Québec, G1V 4G2, Canada.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kamnasaran
keywords: Drug discovery; angiogenesis; microtubule; opioid
references.citation: Cancer Immunol Immunother. 2000 Jul;49(4-5):217-25
references.pmid: 10941904
references.citation: Clin Cancer Res. 2004 Jan 15;10(2):415-27
references.pmid: 14760060
references.citation: Cancer Res. 2002 Jul 15;62(14):4109-14
references.pmid: 12124349
references.citation: Blood. 1999 Dec 15;94(12):4143-55
references.pmid: 10590059
references.citation: Circ Res. 1997 Mar;80(3):383-92
references.pmid: 9048659
references.citation: Curr Med Chem Anticancer Agents. 2002 Jan;2(1):1-17
references.pmid: 12678749
references.citation: Carcinogenesis. 2012 Sep;33(9):1769-81
references.pmid: 22678119
references.citation: Nat Rev Cancer. 2002 Oct;2(10):727-39
references.pmid: 12360276
references.citation: Int J Oncol. 2006 May;28(5):1121-30
references.pmid: 16596228
references.citation: Bioarchitecture. 2012 Nov-Dec;2(6):220-7
references.pmid: 23267416
references.citation: Int J Cancer. 2010 Jan 1;126(1):256-65
references.pmid: 19626589
references.citation: Cancer Cell. 2003 Apr;3(4):363-75
references.pmid: 12726862
references.citation: Bioorg Med Chem. 2006 Oct 1;14(19):6733-6
references.pmid: 16784870
references.citation: Nature. 2000 Sep 14;407(6801):249-57
references.pmid: 11001068
references.citation: Nat Med. 2003 Jun;9(6):653-60
references.pmid: 12778163
references.citation: Clin Cancer Res. 2009 Apr 15;15(8):2594-601
references.pmid: 19351751
references.citation: Science. 1999 Apr 30;284(5415):808-12
references.pmid: 10221914
references.citation: J Surg Res. 2005 May 1;125(1):104-8
references.pmid: 15836858
references.citation: Cancer Lett. 2013 Mar 1;330(1):96-105
references.pmid: 23201138
references.citation: Pathol Oncol Res. 2001;7(2):85-94
references.pmid: 11458270
references.citation: Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1601-6
references.pmid: 9465062
references.citation: Nature. 2011 May 19;473(7347):298-307
references.pmid: 21593862
references.citation: Curr Pharm Des. 2007;13(35):3545-58
references.pmid: 18220791
references.citation: J Pediatr Oncol. 2013;1:32-40
references.pmid: 24749125
references.citation: J Biol Chem. 2012 Aug 31;287(36):30541-51
references.pmid: 22773844
references.citation: Eur J Cancer. 2000 Jun;36(10):1248-57
references.pmid: 10882863
references.citation: Br J Cancer. 1999 Jul;80 Suppl 1:57-64
references.pmid: 10466764
references.citation: Mol Cancer Ther. 2002 Nov;1(13):1191-200
references.pmid: 12479700
references.citation: J Comput Aided Mol Des. 2012 Feb;26(2):233-47
references.pmid: 22170255
references.citation: Tissue Eng Part A. 2010 Oct;16(10):3199-206
references.pmid: 20528673
references.citation: Nat Rev Mol Cell Biol. 2007 Jun;8(6):464-78
references.pmid: 17522591