title: 7b, a novel amonafide analog, inhibited proliferation and phorbol 12-myristate 13-acetate/phytohemagglutinin-induced inflammatory responses of Jurkat T cells via p73-dependent pathway and decrease of nuclear factor-κB DNA-binding, respectively.
abstract: 7b, a novel amonafide analog, has shown high antitumor activity against Raji B-cell lymphoma. We report here that 7b also shows high cytotoxicity against various T lymphoma cells, with the highest IC(50) (concentration for 50% cytotoxicity) value in Jurkat cells. In a previous study, p53-mutant Raji cells were sensitive to 7b treatment. In the present study, the Jurkat T lymphoma cells were characterized as p53-null. Additional assays showed that 7b could induce G1/S phase arrest and mitochondrial apoptosis in Jurkat cells, suggesting 7b as a potential drug candidate for treatment of T-cell lymphoma. This action was not affected by p53 status. Further analysis of molecular mechanisms revealed that up-regulation of p21 and the Bak/Bcl-2 ratio and down-regulation of UHRF1 and c-Myc were attributed to p73 activation. In turn, up-regulation of p73 was initiated by DNA damage-induced reactive oxygen species (ROS) formation. Interestingly, at non-toxic drug concentrations, 7b could also inhibit phorbol 12-myristate 13-acetate/phytohemagglutinin (PMA/PHA)-induced inflammatory responses of Jurkat T cells owing to the suppression of nuclear factor-κB (NF-κB) DNA-binding. Indeed, electrophoretic mobility shift assay and NF-κB binding assay showed that NF-κB DNA-binding was inhibited by 7b, and correspondingly, proinflammatory cytokine production was also decreased. In conclusion, 7b exhibits both antiproliferative and anti-inflammatory activities in T lymphoma cells.
authors: State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors: Jin
authors: J
authors: Shao
authors: Yiquan
authors: Y
authors: Li
authors: Ke
authors: K
authors: Shen
authors: Bing
authors: B
authors: Lin
authors: Yufang
authors: Y
authors: Xu
authors: Yanhua
authors: Y
authors: Lu
authors: Peihao
authors: P
authors: Yin
authors: Qi
authors: Q
authors: Li
authors: Jianwen
authors: J
authors: Liu
authors: Xuhong
authors: X
authors: Qian
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D053644:Naphthalimides / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010835:Phytohemagglutinins; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C558824:6-(dodecylamino)-2-(3-(4-methylpiperazin-1-yl)propyl)-1H-benzo-(de)isoquinoline-1,3(2H)-dione; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D053644:Naphthalimides; D009687:Nuclear Proteins; D010835:Phytohemagglutinins; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C016658:phorbolol myristate acetate; D013755:Tetradecanoylphorbol Acetate