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Marginatoxin induces human hepatoma BEL-7402 cells apoptosis in vitro and in vivo via activation of Fas/FasL-mediated apoptotic pathway

Xiang Hu, De He, Chenjie Zhou, Guolin He, Zhi Zhang, Yuan Cheng, Mingxin Pan, Yi Gao

Marginatoxin, an aryltetraline lactone lignan isolated from Bupleurum marginatum Wall. ex DC (Apiaceae), showed cytotoxic activity against human hepatocellular carcinoma. However, the cytotoxic mechanisms of marginatoxin against cancer cells remained unclear. This study was designed to investigate the detailed mechanism of its cytotoxic effect on human hepatoma BEL-7402 cells by CCK-8, flow cytometry, western blot and xenograft assays. Marginatoxin caused a dose-dependent growth inhibition of BEL-7402 cells with an IC50 of 15.20 μg/ml. Marginatoxin induced BEL-7402 cells apoptosis identified by annexing V/propidium iodide staining kits with the aid of flow cytometry. Marginatoxin-induced apoptosis was characterized by increasing Fas, FasL and Fas associated protein with death domain expression, and cleavage of caspase-8, caspase-10, caspase-3. Furthermore, the results of xenograft assay suggested that marginatoxin inhibited the BEL-7402 cells-induced tumor growth without effect on body weight of nude mice in vivo by regulating the expression levels of above apoptotic proteins. These results demonstrated that marginatoxin could induce apoptosis of human hepatoma BEL-7402 cells in vitro and in vivo through activation of Fas/FasL-mediated apoptotic pathway. All these findings demonstrated that marginatoxin may be a promising chemopreventive agent for treating hepatocellular carcinoma. Moreover, there is a need to further investigate marginatoxin in this regard.