NBBA, a synthetic small molecule, inhibits TNF-alpha-induced angiogenesis by suppressing the NF-kappaB signaling pathway.
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.
Kim
Nam Hee
NH
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.
Jung
Hye Jin
HJ
Shibasaki
Futoshi
F
Kwon
Ho Jeong
HJ
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000187:drug effects / Q000473:pathology
D020533:Angiogenesis Inhibitors; D019086:Bridged Bicyclo Compounds, Heterocyclic; C547207:N-(3-(7-nitro-3-oxobenzo(d)(1,2)selenazol-2(3H)-yl)benzylidene)propan-2-amine oxide; D016328:NF-kappa B; D016566:Organoselenium Compounds; D014409:Tumor Necrosis Factor-alpha; D048670:MAP Kinase Kinase 4