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Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Clarissa Gerhäuser, Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, C010-2 Chemoprevention, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Phone: 49-6221-42-33-06; Fax: 49-6221-42-33-59. E-mail: c.gerhauser{at}dkfz.de

Sulforaphane, an aliphatic isothiocyanate, is a known cancer chemopreventive agent. Aiming to investigate antiangiogenic potential of sulforaphane, we here report a potent decrease of newly formed microcapillaries in a human in vitro antiangiogenesis model, with an IC₅₀ of 0.08 µmol/L. The effects of sulforaphane on endothelial cell functions essential for angiogenesis were investigated in HMEC-1, an immortalized human microvascular endothelial cell line. Molecular signaling pathways leading to activation of endothelial cell proliferation and degradation of the basement membrane were analyzed by reverse transcription-PCR. Sulforaphane showed time- and concentration-dependent inhibitory effects on hypoxia-induced mRNA expression of vascular endothelial growth factor and two angiogenesis-associated transcription factors, hypoxia-inducible factor-1 and c-Myc, in a concentration range of 0.8 to 25 µmol/L. In addition, the expression of the vascular endothelial growth factor receptor KDR/flk-1 was inhibited by sulforaphane at the transcriptional level. Sulforaphane could also affect basement membrane integrity, as it suppressed transcription of the predominant endothelial collagenase matrix metalloproteinase-2 and its tissue inhibitor of metalloproteinase-2. Migration of HMEC-1 cells in a wound healing assay was effectively prevented by sulforaphane at submicromolar concentrations, and we determined an IC₅₀ of 0.69 µmol/L. In addition, within 6 hours of incubation, sulforaphane inhibited tube formation of HMEC-1 cells on basement membrane matrix at 0.1, 1, and 10 µmol/L concentrations. These effects were not due to inhibition of HMEC-1 cell proliferation; however, after 72 hours of incubation, sulforaphane nonselectively reduced HMEC-1 cell growth with an IC₅₀ of 11.3 µmol/L. In conclusion, we have shown that sulforaphane interferes with all essential steps of neovascularization from proangiogenic signaling and basement membrane integrity to endothelial cell proliferation, migration, and tube formation. These novel antiangiogenic activities of sulforaphane are likely to contribute to its cancer chemopreventive and therapeutic potential. [Mol Cancer Ther 2006;5(3):575–85]

Note: The current address for E. Bertl is RCC Ltd., Zelgliweg 1, CH-4452 Itingen, Switzerland.

Received 8/15/05; revised 12/15/05; accepted 1/11/06.

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