title: PPemd26, an anthraquinone derivative, suppresses angiogenesis via inhibiting VEGFR2 signalling.
abstract: OBJECTIVE
  Angiogenesis contributes to coronary heart disease, immune disorders and numerous malignancies. VEGF-A and its receptors (VEGFRs) play a pivotal role in regulating angiogenesis. In an effort to discover more effective inhibitors of tumour angiogenesis, we have analysed the actions of a novel anthraquinone derivative, PPemd26, and explored its anti-angiogenic mechanisms.
  
  
  METHODS
  The effects of PPemd26 were evaluated in vitro using HUVEC cultures to assess proliferation, migration, invasion and tube formation. Immunoblotting was used to analyse phosphorylation of signalling kinases. Effects in vivo were assayed using Matrigel plug and xenograft mouse models.
  
  
  RESULTS
  PPemd26 significantly inhibited VEGF-A-induced proliferation, migration, invasion and tube formation of HUVECs. PPemd26 also attenuated VEGF-A-induced microvessel sprouting from rat aortic rings ex vivo and suppressed formation of new blood vessels in implanted Matrigel plugs in models of angiogenesis in vivo. In addition, PPemd26 inhibited VEGF-A-induced phosphorylation of VEGFR2 and its downstream protein kinases including Akt, focal adhesion kinase, ERK and Src. Furthermore, systemic administration of PPemd26 suppressed the growth of s.c. xenografts of human colon carcinoma in vivo. Histochemical analysis of the xenografts revealed a marked reduction in stainingfor the vascular marker CD31 and proliferation marker Ki-67.
  
  
  CONCLUSIONS
  This study provides evidence that PPemd26 suppressed tumour angiogenesis through inhibiting VEGFR2 signalling pathways, suggesting that PPemd26 is a potential drug candidate for developing anti-angiogenic agents for the treatment of cancer and angiogenesis-related diseases.
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: S W
authors.initials: SW
authors.lastname: Huang
authors.forename: J C
authors.initials: JC
authors.lastname: Lien
authors.forename: S C
authors.initials: SC
authors.lastname: Kuo
authors.forename: T F
authors.initials: TF
authors.lastname: Huang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects; D002277:Carcinoma; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival; D003110:Colonic Neoplasms; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000254:growth & development; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000880:Anthraquinones; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C538818:1,8-dinitro-4,5-dihydroxyanthraquinone
references.citation: J Mol Signal. 2008 Mar 31;3:8
references.pmid: 18377662
references.citation: Nature. 2000 Feb 3;403(6769):503-11
references.pmid: 10676951
references.citation: Curr Opin Pharmacol. 2008 Aug;8(4):427-32
references.pmid: 18625340
references.citation: Cancer Res. 2008 Apr 1;68(7):2375-83
references.pmid: 18381445
references.citation: J Clin Invest. 2005 Oct;115(10):2618-24
references.pmid: 16200194
references.citation: J Thyroid Res. 2011;2011:815826
references.pmid: 21687607
references.citation: Adv Cancer Res. 2007;97:203-24
references.pmid: 17419947
references.citation: J Immunol. 2010 Jul 15;185(2):1215-21
references.pmid: 20548028
references.citation: Nat Med. 2003 Jun;9(6):669-76
references.pmid: 12778165
references.citation: J Biol Chem. 2000 Feb 18;275(7):5096-103
references.pmid: 10671553
references.citation: J Biol Chem. 2005 May 20;280(20):19867-74
references.pmid: 15772071
references.citation: Nat Rev Cancer. 2004 Nov;4(11):839-49
references.pmid: 15516957
references.citation: Br J Cancer. 2007 Jun 18;96(12):1788-95
references.pmid: 17519900
references.citation: Clin Cancer Res. 2011 Jul 1;17(13):4439-50
references.pmid: 21622720
references.citation: Br J Pharmacol. 2013 Oct;170(4):807-21
references.pmid: 23848338
references.citation: J Cell Biol. 2002 Apr 1;157(1):149-60
references.pmid: 11927607
references.citation: Prostate. 2004 Sep 1;60(4):367-71
references.pmid: 15264249
references.citation: Carcinogenesis. 2012 May;33(5):1022-30
references.pmid: 22436611
references.citation: Nat Rev Mol Cell Biol. 2006 May;7(5):359-71
references.pmid: 16633338
references.citation: J Clin Oncol. 2007 Jul 20;25(21):3045-54
references.pmid: 17634482
references.citation: Mol Cancer Ther. 2008 Nov;7(11):3509-18
references.pmid: 19001434
references.citation: Cancer Res. 2006 Dec 15;66(24):11851-8
references.pmid: 17178882
references.citation: Oncologist. 2004;9 Suppl 1:2-10
references.pmid: 15178810
references.citation: Haematologica. 2010 Jun;95(6):1004-15
references.pmid: 20145274
references.citation: Drug Discov Today. 2011 Mar;16(5-6):219-28
references.pmid: 21262381
references.citation: PLoS One. 2012;7(10):e46869
references.pmid: 23056499
references.citation: Biochem Pharmacol. 2002 Dec 15;64(12):1713-24
references.pmid: 12445860
references.citation: Am J Pathol. 2003 Jun;162(6):1913-26
references.pmid: 12759248
references.citation: Aging (Albany NY). 2011 Mar;3(3):192-222
references.pmid: 21422497
references.citation: Br J Pharmacol. 2013 Dec;170(8):1676-705
references.pmid: 24528241
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D1098-106
references.pmid: 24234439
references.citation: Br J Pharmacol. 2013 Dec;170(8):1797-867
references.pmid: 24528243
references.citation: Br J Pharmacol. 2010 Aug;160(7):1577-9
references.pmid: 20649561
references.citation: Nat Rev Clin Oncol. 2009 Oct;6(10):569-79
references.pmid: 19736552
references.citation: Cardiovasc Res. 2005 Feb 15;65(3):587-98
references.pmid: 15664385
references.citation: Blood. 2013 Sep 5;122(10):1822-32
references.pmid: 23896411
references.citation: Eur J Pharmacol. 2006 Dec 28;553(1-3):46-53
references.pmid: 17056031
references.citation: Science. 2004 Mar 19;303(5665):1800-5
references.pmid: 15031492
references.citation: Science. 2004 Jun 4;304(5676):1497-500
references.pmid: 15118125
references.citation: Mol Cell. 1999 Dec;4(6):915-24
references.pmid: 10635317
references.citation: Thromb Res. 2010 Apr;125 Suppl 2:S55-7
references.pmid: 20434006
references.citation: Br J Pharmacol. 2010 Aug;160(7):1573-6
references.pmid: 20649560
references.citation: Nat Clin Pract Oncol. 2006 Dec;3(12):682-92
references.pmid: 17139319
references.citation: Nat Rev Cancer. 2006 Aug;6(8):626-35
references.pmid: 16837971
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11393-8
references.pmid: 12177445
references.citation: J Biol Chem. 2003 Sep 19;278(38):36661-8
references.pmid: 12844492
references.citation: Oncology. 2005;69 Suppl 3:4-10
references.pmid: 16301830
references.citation: J Clin Invest. 2011 Jul;121(7):2668-78
references.pmid: 21633168
references.citation: Br J Pharmacol. 2001 Sep;134(1):11-20
references.pmid: 11522592
references.citation: Blood. 2004 Jun 15;103(12):4536-44
references.pmid: 14982870
references.citation: Lancet Oncol. 2009 Oct;10(10):967-74
references.pmid: 19767240
references.citation: J Thromb Haemost. 2005 Aug;3(8):1835-42
references.pmid: 16102050
references.citation: Nature. 1994 Jan 27;367(6461):375-6
references.pmid: 7906866
references.citation: Nat Rev Cancer. 2003 Jun;3(6):401-10
references.pmid: 12778130
references.citation: Drugs Today (Barc). 2011 Nov;47(11):857-68
references.pmid: 22146228
references.citation: Nature. 2000 Sep 14;407(6801):249-57
references.pmid: 11001068
references.citation: Nature. 2005 Dec 15;438(7070):967-74
references.pmid: 16355214
references.citation: Atherosclerosis. 2007 Mar;191(1):33-9
references.pmid: 16725144
references.citation: Cancer Res. 2000 Jun 1;60(11):2800-4
references.pmid: 10850417
references.citation: J Clin Oncol. 2006 Jan 1;24(1):25-35
references.pmid: 16314617
references.citation: Carcinogenesis. 2010 Mar;31(3):481-8
references.pmid: 19969552