Abstract
Cepharanthine (CEP), a biscoclaurine alkaloid, has been reported to induce cell death, however, the molecular mechanism of this phenomenon remains unclear. We herein report that CEP induced apoptosis in HuH-7 cells through nuclear fragmentation, DNA ladder formation, cytochrome c release, caspase-3 activation and poly-(ADP-ribose)-polymerase cleavage. CEP triggered the generation of reactive oxygen intermediates, the activation of mitogen activated protein kinase (MAPK) p38, JNK1/2 and p44/42, and the downregulation of protein kinase B/Akt. Antioxidants and SP600125, an inhibitor of JNK1/2, but not inhibitors of p38 MAPK and MEK1/2, significantly prevented cell death, thus implying that reactive oxygen species and JNK1/2 play crucial roles in the CEP-induced apoptosis of HuH-7 cells.
MeSH terms
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Alkaloids / metabolism*
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Animals
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Anthracenes / metabolism
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Anti-Inflammatory Agents, Non-Steroidal / metabolism*
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Apoptosis / physiology*
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Benzylisoquinolines
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Carcinoma, Hepatocellular*
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Caspase 3
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Caspases / metabolism
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Cell Line, Tumor
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Collagen Type XI / metabolism
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Cytochromes c / metabolism
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Down-Regulation
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Enzyme Activation
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Enzyme Inhibitors / metabolism
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Humans
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Liver Neoplasms*
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Mitogen-Activated Protein Kinase 8 / metabolism*
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Mitogen-Activated Protein Kinase 9 / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism*
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Reactive Oxygen Species / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Alkaloids
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Anthracenes
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Anti-Inflammatory Agents, Non-Steroidal
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Benzylisoquinolines
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COL11A2 protein, human
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Collagen Type XI
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Enzyme Inhibitors
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Reactive Oxygen Species
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pyrazolanthrone
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cepharanthine
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Cytochromes c
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Mitogen-Activated Protein Kinase 9
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases
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CASP3 protein, human
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Caspase 3
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Caspases