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

Leuk Lymphoma. 2013 Feb;54(2):359-71. doi: 10.3109/10428194.2012.708750. Epub 2012 Sep 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytokines / biosynthesis
  • DNA Damage
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation Mediators / metabolism
  • Jurkat Cells
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • NF-kappa B / metabolism*
  • Naphthalimides / pharmacology*
  • Nuclear Proteins / metabolism*
  • Oxidation-Reduction / drug effects
  • Phytohemagglutinins
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Reactive Oxygen Species / metabolism
  • Tetradecanoylphorbol Acetate / analogs & derivatives
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Proteins / metabolism*

Substances

  • 6-(dodecylamino)-2-(3-(4-methylpiperazin-1-yl)propyl)-1H-benzo-(de)isoquinoline-1,3(2H)-dione
  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Cytokines
  • DNA-Binding Proteins
  • Inflammation Mediators
  • NF-kappa B
  • Naphthalimides
  • Nuclear Proteins
  • Phytohemagglutinins
  • Proto-Oncogene Proteins c-myc
  • Reactive Oxygen Species
  • TP73 protein, human
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • phorbolol myristate acetate
  • Tetradecanoylphorbol Acetate