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 micromol/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-1alpha and c-Myc, in a concentration range of 0.8 to 25 micromol/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 micromol/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 micromol/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 micromol/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.

译文

萝卜硫素,一种脂肪族异硫氰酸酯,是一种已知的癌症化学预防剂。为了研究萝卜硫素的抗血管生成潜力,我们在这里报告了在人体外抗血管生成模型中新形成的微毛细血管的有效减少,IC50为0.08 micromol/L。在永生化的人微血管内皮细胞系HMEC-1中研究了萝卜硫素对血管生成必不可少的内皮细胞功能的影响。通过逆转录PCR分析了导致内皮细胞增殖激活和基底膜降解的分子信号通路。萝卜硫素对缺氧诱导的血管内皮生长因子和两种血管生成相关转录因子 (低氧诱导factor-1alpha和c-Myc) 的mRNA表达具有时间和浓度依赖性的抑制作用,浓度范围为0.8至25微摩尔/升。此外,在转录水平上,萝卜硫素抑制了血管内皮生长因子受体KDR/flk-1的表达。萝卜硫素也可能影响基底膜的完整性,因为它抑制了主要的内皮胶原酶基质metalloproteinase-2及其组织metalloproteinase-2抑制剂的转录。亚微摩尔浓度的萝卜硫素有效地防止了伤口愈合试验中HMEC-1细胞的迁移,我们确定的IC50为0.69 micromol/L。此外,在孵育的6小时内,萝卜硫素以0.1、1和10 micromol/L的浓度抑制基底膜基质上HMEC-1细胞的管形成。这些作用不是由于抑制HMEC-1细胞增殖; 然而,在孵育72小时后,萝卜硫素非选择性地降低了HMEC-1细胞的生长,IC50为11.3微摩尔/升。总之,我们已经表明,萝卜硫烷干扰了从促血管生成信号和基底膜完整性到内皮细胞增殖,迁移和管形成的所有重要新生血管步骤。萝卜硫素的这些新的抗血管生成活性可能有助于其癌症的化学预防和治疗潜力。

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