title: 6"-Debromohamacanthin A, a bis (indole) alkaloid, inhibits angiogenesis by targeting the VEGFR2-mediated PI3K/AKT/mTOR signaling pathways.
abstract: Hamacanthins, bis (indole) alkaloids, are found in a few marine sponges, including Spongosorites sp. Hamacanthins have been shown to possess cytotoxic, antibacterial and antifungal activities. However, the precise mechanism for the biological activities of hamacanthins has not yet been elucidated. In the present study, the anti-angiogenic effects of 6"-debromohamacanthin A (DBHA), an active component of isolated hamacanthins, were evaluated in cultured human umbilical vascular endothelial cells (HUVEC) and endothelial-like cells differentiated from mouse embryonic stem (mES) cells. DBHA significantly inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration and tube formation in the HUVEC. DBHA also suppressed the capillary-like structure formation and the expression of platelet endothelial cell adhesion molecule (PECAM), an endothelial biomarker, in mES cell-derived endothelial-like cells. To further understand the precise molecular mechanism of action, VEGF-mediated signaling pathways were analyzed in HUVEC cells and mES cell-derived endothelial-like cells. DBHA suppressed the VEGF-induced expression of MAPKs (p38, ERK and SAPK/JNK) and the PI3K/AKT/mTOR signaling pathway. In addition, DBHA inhibited microvessel sprouting in mES/EB-derived embryoid bodies. In an ex vivo model, DBHA also suppressed the microvessel sprouting of mouse aortic rings. The findings suggest for the first time that DBHA inhibits angiogenesis by targeting the vascular endothelial growth factor receptor 2 (VEGFR2)-mediated PI3K/AKT/mTOR signaling pathway in endothelial cells.
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, San 56-1 Sillim-dong, Gwanak-gu, Seoul 151-742, Korea. gidaekim@snu.ac.kr
authors.forename: Gi Dae
authors.initials: GD
authors.lastname: Kim
authors.forename: Oug Jae
authors.initials: OJ
authors.lastname: Cheong
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Bae
authors.forename: Jongheon
authors.initials: J
authors.lastname: Shin
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011161:Porifera / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D026121:Indole Alkaloids; D019869:Phosphatidylinositol 3-Kinases; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; C585606:6''-debromohamacanthin A
references.citation: Biochem Biophys Res Commun. 2000 Feb 5;268(1):183-91
references.pmid: 10652234
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1076-81
references.pmid: 15644447
references.citation: Nat Rev Cancer. 2005 Jun;5(6):423-35
references.pmid: 15928673
references.citation: Bioorg Med Chem Lett. 2005 Nov 15;15(22):4927-31
references.pmid: 16154746
references.citation: Toxicol In Vitro. 2009 Jun;23(4):719-27
references.pmid: 19272435
references.citation: APMIS. 2004 Jul-Aug;112(7-8):496-507
references.pmid: 15563312
references.citation: Development. 1988 Mar;102(3):471-8
references.pmid: 2460305
references.citation: Cardiovasc Res. 2006 Feb 1;69(2):512-9
references.pmid: 16336951
references.citation: Nat Protoc. 2011 Dec 22;7(1):89-104
references.pmid: 22193302
references.citation: FEBS Lett. 2003 Feb 11;536(1-3):19-24
references.pmid: 12586331
references.citation: Trends Pharmacol Sci. 2001 Apr;22(4):201-7
references.pmid: 11282421
references.citation: J Biol Chem. 2010 Jan 1;285(1):80-94
references.pmid: 19864431
references.citation: Cancer Biol Ther. 2008 Dec;7(12):1994-2003
references.pmid: 18981713
references.citation: Lab Invest. 1998 Oct;78(10):1301-14
references.pmid: 9800956
references.citation: J Nat Prod. 2005 May;68(5):711-5
references.pmid: 15921415
references.citation: FEBS Lett. 2001 Apr 6;494(1-2):125-8
references.pmid: 11297748
references.citation: J Nat Prod. 1999 Apr;62(4):647-9
references.pmid: 10217734
references.citation: J Nat Prod. 2004 Aug;67(8):1216-38
references.pmid: 15332835
references.citation: Cancer Res. 2008 Mar 15;68(6):1843-50
references.pmid: 18339865
references.citation: Mol Pharmacol. 2006 Apr;69(4):1226-33
references.pmid: 16424078
references.citation: Oncogene. 2004 Jan 8;23(1):192-200
references.pmid: 14712224
references.citation: Cell Physiol Biochem. 2012;30(3):758-70
references.pmid: 22890153
references.citation: Toxicol In Vitro. 2007 Dec;21(8):1631-40
references.pmid: 17719739
references.citation: Toxicol Lett. 2008 Aug 28;180(3):166-73
references.pmid: 18590808
references.citation: Exp Cell Res. 2009 Jun 10;315(10):1668-82
references.pmid: 19285068
references.citation: Circ Res. 2002 Jun 28;90(12):1243-50
references.pmid: 12089061
references.citation: Am J Pathol. 2011 Jan;178(1):336-44
references.pmid: 21224070
references.citation: Curr Opin Pharmacol. 2008 Aug;8(4):393-412
references.pmid: 18721898
references.citation: Future Oncol. 2009 Apr;5(3):291-303
references.pmid: 19374536
references.citation: Proc Natl Acad Sci U S A. 1981 Dec;78(12):7634-8
references.pmid: 6950406
references.citation: Biol Pharm Bull. 2009 Jul;32(7):1261-5
references.pmid: 19571395
references.citation: J Nat Prod. 1994 Oct;57(10):1437-41
references.pmid: 7807127
references.citation: Mol Cancer Ther. 2008 Jul;7(7):1789-96
references.pmid: 18644991
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Kango Gijutsu. 1980 Nov;26(15):2047-50
references.pmid: 6904613
references.citation: Curr Med Chem. 2008;15(12):1192-208
references.pmid: 18473813
references.citation: Am J Physiol Cell Physiol. 2006 Aug;291(2):C317-26
references.pmid: 16825603
references.citation: Oncogene. 2000 Apr 20;19(17):2138-46
references.pmid: 10815805
references.citation: Trends Immunol. 2003 Jun;24(6):327-34
references.pmid: 12810109
references.citation: Nature. 1992 Oct 29;359(6398):845-8
references.pmid: 1279432
references.citation: Am J Pathol. 2000 Jan;156(1):151-8
references.pmid: 10623662
references.citation: Cancer. 2012 Jul 15;118(14):3455-67
references.pmid: 22086782