In Vitro Toxicity Of 7-b In Raji Cells And Jurkat Cells

Previous studies have shown that 7-b (6-(Dodecylamino)-2-(3-(4-methylpiperazin-1-yl)propyl)-1H-benzo-[de]isoquinoline-1,3(2H)-dione), a novel amonafide-based DNA intercalator, was generated as a new anticancer candidate. However, the effects induced by 7-b and the molecular mechanisms involved remain poorly understood in Raji cells and Jurkat cells. To shed light on these issues, we have investigated the effects of 7-b on proliferation, cell cycle progression, apoptosis activity and oxidative stress levels of lymphoma Raji cells and Jurkat cells in vitro. Our results showed that 7-b inhibited the proliferation of Raji cells and Jurkat cells and induced Gl cell cycle arrest in a dose-dependent manner. Moreover,7-b treatment triggered programmed cell death, production of reactive oxygen species (ROS) and alteration of the mitochondrial membrane potential. Further analysis of the expression pattern of a key set of cell cycle regulators revealed that 7-b strongly inhibited the expression of c-Myc, p53, PCNA(proliferating cell nuclear antigen) and CDK2 and induced the expression of p21 in a concentration-and time-dependent manner in Raji cells, but 7-b strongly inhibited the expression of c-Myc, p73 and UHRF1 and induced the expression of p21 in a concentration-and time-dependent manner in Jurkat cells.7-b triggered the mitochondrial apoptotic pathway indicated by enhanced Bax-to-Bcl-2 expression ratio, ROS generation, loss of mitochondrial membrane potential. Here, we also showed that 7-b had a profound inhibitory effect on IL-2 production in Jurkat T cells. Moreover,7-b inhibited COX-2 expression and the NF-κB-DNA binding of the nuclear extracts obtained from the PHA/PMA-stimulated Jurkat T cells. Altogether our results showed that 7-b mediated its growth inhibitory effects on Raji cells via the activation of a ROS-mediated mitochondrial pathway and cell cycle checkpoint signaling pathway which subsequently targeted p21.We also found 7-b mediated its growth inhibitory effects on jurkat cells via the activation of a ROS-mediated mitochondrial pathway and cell cycle checkpoint signaling pathway which subsequently targeted p73. The immunosuppressive effect of 7-b on activated T cells was presumably through modulation of COX-2 expression and the NF-κB-DNA binding of the nuclear extracts. Thus,7-b might be defined as a new immunosuppressive compound suited for the treatment of deregulated and unwanted B cell and T cell-mediated immune responses.