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      ROS-mediated JNK/p38-MAPK activation regulates Bax translocation in Sorafenib-induced apoptosis of EBV-transformed B cells.

      International Journal of Oncology
      Apoptosis, drug effects, B-Lymphocytes, metabolism, virology, Herpesvirus 4, Human, genetics, Humans, MAP Kinase Signaling System, Membrane Potential, Mitochondrial, Mitochondria, Neoplasms, drug therapy, pathology, Niacinamide, administration & dosage, analogs & derivatives, Phenylurea Compounds, Phosphatidylinositol 3-Kinases, Phosphorylation, Reactive Oxygen Species, bcl-2-Associated X Protein, p38 Mitogen-Activated Protein Kinases

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          Abstract

          Sorafenib (SRF) is a multi-kinase inhibitor that has been shown to have antitumor activity against several types of cancers, but the effect of SRF on EBV-transformed B cells is unknown. We report that SRF can induce the apoptosis of EBV-transformed B cells through JNK/p38-MAPK activation. SRF triggered the generation of reactive oxygen species (ROS), translocation of Bax into the mitochondria, disruption of mitochondrial membrane potential, activation of caspase-9, caspase-3 and PARP, and subsequent apoptosis. Moreover, we found that SRF exposure activated the phosphorylation of JNK and p38-MAPK and suppressed the phosphorylation of PI3K-p85 and Akt. N-acetyl-l-cysteine (NAC) inhibited the activation of JNK and p38-MAPK. SP600125 and SB203580 blocked apoptosis and mitochondrial membrane disruption but did not affect ROS production after SRF treatment. These findings provide novel insights into the molecular mechanisms driving SRF-mediated cell death and suggest that SRF could be a potential therapeutic drug for the treatment of EBV-related malignant diseases.

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