This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sauer, H. Articles by Wartenberg, M. Search for Related Content PubMed PubMed Citation Articles by Sauer, H. Articles by Wartenberg, M.

(American Journal of Pathology. 2000;156:151-158.)
© 2000 American Society for Investigative Pathology

Regular Articles

Thalidomide Inhibits Angiogenesis in Embryoid Bodies by the Generation of Hydroxyl Radicals

From the Department of Neurophysiology, University of Cologne, Cologne, Germany

Thalidomide is a teratogen with anti-angiogenic properties and causes stunted limb growth (dysmelia) during human embryogenesis. The molecular mechanisms of thalidomide action in embryopathy are currently unknown. Using the endothelial-specific antigen platelet endothelial cell adhesion molecule-1 and confocal laser scanning microscopy we have demonstrated that thalidomide exerts anti-angiogenic effects on the development of capillary structures in embryoid bodies differentiated from murine embryonic stem cells. Consequently, in thalidomide-treated embryoid bodies the diffusion properties of the tissue were deteriorated. Thalidomide raised reactive oxygen species (ROS), as revealed using 2'7'-dichlorodihydrofluorescein diacetate (H₂DCF-DA) as an indicator. A comparable ROS generation was achieved with the thalidomide hydrolysis product phthaloyl glutamic acid (PGA), but not with phthalimide (PI), the major component of thalidomide. ROS formation by thalidomide was inhibited by the hydroxyl radical scavengers mannitol and 2-mercaptoethanol. After coadministration of either 2-mercaptoethanol or mannitol with thalidomide the anti-angiogenic effects of thalidomide were abolished and the diffusion properties of the tissue were restored to the control values. In summary, our data suggest that thalidomide exerts its anti-angiogenic properties via the generation of toxic hydroxyl radicals, which impair vasculogenesis and angiogenesis during embryoid body development.

This article has been cited by other articles:

				W. Aerbajinai, J. Zhu, Z. Gao, K. Chin, and G. P. Rodgers Thalidomide induces {gamma}-globin gene expression through increased reactive oxygen species mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis Blood, October 15, 2007; 110(8): 2864 - 2871. [Abstract] [Full Text] [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]

				A. Vacca, C. Scavelli, V. Montefusco, G. Di Pietro, A. Neri, M. Mattioli, S. Bicciato, B. Nico, D. Ribatti, F. Dammacco, et al. Thalidomide Downregulates Angiogenic Genes in Bone Marrow Endothelial Cells of Patients With Active Multiple Myeloma J. Clin. Oncol., August 10, 2005; 23(23): 5334 - 5346. [Abstract] [Full Text] [PDF]

				T. Yabu, H. Tomimoto, Y. Taguchi, S. Yamaoka, Y. Igarashi, and T. Okazaki Thalidomide-induced antiangiogenic action is mediated by ceramide through depletion of VEGF receptors, and is antagonized by sphingosine-1-phosphate Blood, July 1, 2005; 106(1): 125 - 134. [Abstract] [Full Text] [PDF]

				A. M. Wobus and K. R. Boheler Embryonic Stem Cells: Prospects for Developmental Biology and Cell Therapy Physiol Rev, April 1, 2005; 85(2): 635 - 678. [Abstract] [Full Text] [PDF]

				P. Magnusson, C. Rolny, L. Jakobsson, C. Wikner, Y. Wu, D. J. Hicklin, and L. Claesson-Welsh Deregulation of Flk-1/vascular endothelial growth factor receptor-2 in fibroblast growth factor receptor-1-deficient vascular stem cell development J. Cell Sci., March 15, 2004; 117(8): 1513 - 1523. [Abstract] [Full Text] [PDF]

				M. Miyata, E. Tamura, K. Motoki, K. Nagata, and Y. Yamazoe Thalidomide-induced Suppression of Embryo Fibroblast Proliferation Requires CYP1A1-Mediated Activation Drug Metab. Dispos., April 1, 2003; 31(4): 469 - 475. [Abstract] [Full Text] [PDF]

				A. Gupta, B.H. Cohen, P. Ruggieri, R.J. Packer, and P.C. Phillips Phase I study of thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1 Neurology, January 14, 2003; 60(1): 130 - 132. [Abstract] [Full Text] [PDF]

				S. Yaccoby, C. L. Johnson, S. C. Mahaffey, M. J. Wezeman, B. Barlogie, and J. Epstein Antimyeloma efficacy of thalidomide in the SCID-hu model Blood, December 1, 2002; 100(12): 4162 - 4168. [Abstract] [Full Text] [PDF]

				N Eter and M Spitznas DMSO mimics inhibitory effect of thalidomide on choriocapillary endothelial cell proliferation in culture Br. J. Ophthalmol., November 1, 2002; 86(11): 1303 - 1305. [Abstract] [Full Text] [PDF]

				J. M. Hansen, K. K. Harris, M. A. Philbert, and C. Harris Thalidomide Modulates Nuclear Redox Status and Preferentially Depletes Glutathione in Rabbit Limb versus Rat Limb J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 768 - 776. [Abstract] [Full Text] [PDF]

				J. A. Keifer, D. C. Guttridge, B. P. Ashburner, and A. S. Baldwin Jr. Inhibition of NF-kappa B Activity by Thalidomide through Suppression of Ikappa B Kinase Activity J. Biol. Chem., June 15, 2001; 276(25): 22382 - 22387. [Abstract] [Full Text] [PDF]