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Blood, 1 July 2005, Vol. 106, No. 1, pp. 125-134. Prepublished online as a Blood First Edition Paper on March 1, 2005; DOI 10.1182/blood-2004-09-3679. This Article Full Text (PDF) All Versions of this Article: 2004-09-3679v1 106/1/125    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yabu, T. Articles by Okazaki, T. Search for Related Content PubMed PubMed Citation Articles by Yabu, T. Articles by Okazaki, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 24, 2004 Accepted February 16, 2005 Thalidomide-induced anti-angiogenic action is mediated by ceramide through depletion of VEGF receptors, and antagonized by sphingosine-1-phosphate Takeshi Yabu, Hidekazu Tomimoto, Yoshimitsu Taguchi, Syohei Yamaoka, Yasuyuki Igarashi, and Toshiro Okazaki* Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutics, Hokkaido University, Sapporo, Hokkaido, Japan Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan; Department of Hematology/Clinical Laboratory Medicine, School of Medicine, Tottori University, Yonago City, Tottori, Japan * Corresponding author; email: toshiroo{at}grape.med.tottori-u.ac.jp. Thalidomide, which is clinically recognized as an efficient therapeutic agent for multiple myeloma, has been thought to exert anti-angiogenic action through unknown mechanism. We here show a novel mechanism of thalidomide-induced anti-angiogenesis in zebrafish embryos. Thalidomide induces the defect of major blood vessels, which is demonstrated by their morphological loss and confirmed by the depletion of vascular endothelial growth factor (VEGF) receptors such as neuropilin-1 and Flk-1. Transient increase of ceramide content through activation of neutral sphingomyelinase (nSMase) precedes thalidomide-induced vascular defect in the embryos. Synthetic cell permeable ceramide, N-acetylsphingosine (C2-ceramide) inhibits embryonic angiogenesis as well as thalidomide. The blockade of ceramide generation by anti-sense morpholino oligonucleotides for nSMase prevents thalidomaide-induced ceramide generation and vascular defect. In contrast to ceramide, sphingosine-1-phosphate (S1P) inhibits nSMase-dependent ceramide generation and restores thalidomide-induced embryonic vascular defect with increase of expression of VEGF receptors. In human umbilical vein endothelial cells (HUVECs), thalidomide-induced inhibition of cell growth, generation of ceramide through nSMase and depletion of VEGF receptors are restored to the control levels by pretreatment with S1P. These results suggest that thalidomide-induced anti-angiogenic action is regulated by the balance between ceramide and S1P signal. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Yabu, A. Shimuzu, and M. Yamashita A Novel Mitochondrial Sphingomyelinase in Zebrafish Cells J. Biol. Chem., July 24, 2009; 284(30): 20349 - 20363. [Abstract] [Full Text] [PDF] D. C. Johnson, S. Corthals, C. Ramos, A. Hoering, K. Cocks, N. J. Dickens, J. Haessler, H. Goldschmidt, J. A. Child, S. E. Bell, et al. Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping Blood, December 15, 2008; 112(13): 4924 - 4934. [Abstract] [Full Text] [PDF] T. Yabu, S. Imamura, M. Yamashita, and T. Okazaki Identification of Mg2+-dependent Neutral Sphingomyelinase 1 as a Mediator of Heat Stress-induced Ceramide Generation and Apoptosis J. Biol. Chem., October 31, 2008; 283(44): 29971 - 29982. [Abstract] [Full Text] [PDF] P. Rubegni, S. Poggiali, R. Bilenchi, A. Diana, M. Risulo, L. Civeli, and M. Fimiani Venous Ulcers of the Lower Limbs Due to Congenital Thalidomide-Related Valve Defect Angiology, September 1, 2007; 58(4): 491 - 493. [Abstract] [PDF] D. Mannheim, D. Versari, E. Daghini, M. Gossl, O. Galili, A. Chade, V. S. Rajkumar, E. L. Ritman, L. O. Lerman, and A. Lerman Impaired myocardial perfusion reserve in experimental hypercholesterolemia is independent of myocardial neovascularization Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2449 - H2458. [Abstract] [Full Text] [PDF] J. H. Chidlow Jr., W. Langston, J. J.M. Greer, D. Ostanin, M. Abdelbaqi, J. Houghton, A. Senthilkumar, D. Shukla, A. P. Mazar, M. B. Grisham, et al. Differential Angiogenic Regulation of Experimental Colitis Am. J. Pathol., December 1, 2006; 169(6): 2014 - 2030. [Abstract] [Full Text] [PDF] S. Shalapour, A. Zelmer, M. Pfau, E. Moderegger, C. Costa-Blechschmidt, F. K.H. van Landeghem, T. Taube, I. Fichtner, C. Buhrer, G. Henze, et al. The Thalidomide Analogue, CC-4047, Induces Apoptosis Signaling and Growth Arrest in Childhood Acute Lymphoblastic Leukemia Cells In vitro and In vivo. Clin. Cancer Res., September 15, 2006; 12(18): 5526 - 5532. [Abstract] [Full Text] [PDF] L. M. Ellis The role of neuropilins in cancer Mol. Cancer Ther., May 1, 2006; 5(5): 1099 - 1107. [Abstract] [Full Text] [PDF] E. Gulbins and P. L. Li Physiological and pathophysiological aspects of ceramide Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R11 - R26. [Abstract] [Full Text] [PDF]

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