Chemical Genomics Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Biochem Biophys Res Commun. 2010 Jan 15;391(3):1500-5. doi: 10.1016/j.bbrc.2009.12.101. Epub 2009 Dec 24.
Nuclear factor-kappaB (NF-kappaB) is a crucial transcription factor that contributes to cancer development by regulating a number of genes involved in angiogenesis and tumorigenesis. Here, we describe (Z)-N-(3-(7-nitro-3-oxobenzo[d][1,2]selenazol-2(3H)-yl)benzylidene)propan-2-amine oxide (NBBA) as a new anti-angiogenic small molecule that targets NF-kappaB activity. NBBA showed stronger growth inhibition on human umbilical vein endothelial cells (HUVECs) than on the cancer cell lines we tested. Moreover, NBBA inhibited tumor necrosis factor-alpha (TNF-alpha)-induced tube formation and invasion of HUVECs. In addition, NBBA suppressed the neovascularization of chorioallantonic membrane from growing chick embryos in vivo. To address the mode of action of the compound, the effect of NBBA on TNF-alpha-induced NF-kappaB transcription activity was investigated. NBBA suppressed TNF-alpha-induced c-Jun N-terminal kinase phosphorylation, which resulted in suppression of transcription of NF-kappaB and its target genes, including interleukin-8, interleukin-1alpha, and epidermal growth factor. Collectively, these results demonstrated that NBBA is a new anti-angiogenic small molecule that targets the NF-kappaB signaling pathway.
核因子-κB（NF-κB）是一种关键的转录因子，通过调节参与血管生成和肿瘤发生的许多基因，促进癌症的发展。在这里，我们描述了（Z）-N-（3-（7-硝基-3-氧代苯并[d][1,2]硒唑-2（3H）-基）苄叉）丙-2-胺氧化物（NBBA）作为一种针对 NF-κB 活性的新型抗血管生成小分子。NBBA 对人脐静脉内皮细胞（HUVEC）的生长抑制作用强于我们测试的癌细胞系。此外，NBBA 抑制肿瘤坏死因子-α（TNF-α）诱导的 HUVEC 管形成和侵袭。此外，NBBA 抑制了体内生长鸡胚绒毛尿囊膜的新血管生成。为了解决该化合物的作用模式，研究了 NBBA 对 TNF-α诱导的 NF-κB 转录活性的影响。NBBA 抑制了 TNF-α诱导的 c-Jun N-末端激酶磷酸化，从而抑制了 NF-κB 及其靶基因，包括白细胞介素-8、白细胞介素-1α和表皮生长因子的转录。总之，这些结果表明 NBBA 是一种针对 NF-κB 信号通路的新型抗血管生成小分子。
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