Abstract
Evidence suggests that mistletoe extract has the potential to be used as an anticancer agent. Abnobaviscum F® is a European mistletoe extract from the host tree Fraxinus. We investigated the effect of Abnobaviscum F on the growth and survival of different leukemia cell lines. Abnobaviscum F treatment strongly reduced survival and induced apoptosis of K562 (human myeloid leukemia), RPMI-8226 (human plasmacytoma) and L1210 (murine lymphocytic leukemia) cells in culture. Using K562 cells to further investigate the mechanism of action of Abnobaviscum F, we showed that Abnobaviscum F-induced cell death was associated with the activation of caspase-9, JNK-1/2 and p38 MAPK, as well as with the downregulation of Mcl-1, and inhibition of ERK-1/2 and PKB phosphorylation. Moreover, Abnobaviscum F treatment led to both a reduction of cellular glutathione (GSH) and the induction of ER stress (GRP78 and CHOP induction and eIF-2α phosphorylation). By contrast, Abnobaviscum F did not impact the expression of the DR4 and DR5 death receptors. The Abnobaviscum F-induced apoptosis of K562 cells was blocked by pretreatment with either GSH, z-VAD-fmk or SP600125. Our results, therefore, show that Abnobaviscum F induces apoptosis of K562 cells through the activation of the intrinsic caspase pathway, the phosphorylation of JNK-1, the reduction of cellular GSH, and the induction of ER stress.
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Anthracenes / pharmacology
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Apoptosis / drug effects*
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Caspase 9 / biosynthesis
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Caspase 9 / metabolism
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Cell Line, Tumor
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DNA Fragmentation / drug effects
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Down-Regulation / drug effects
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum Stress / drug effects
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Eukaryotic Initiation Factor-2 / metabolism
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Extracellular Signal-Regulated MAP Kinases / biosynthesis
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Glutathione / metabolism
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Glutathione / pharmacology
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Heat-Shock Proteins / biosynthesis
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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K562 Cells
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Leukemia, Lymphoid / metabolism
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Leukemia, Lymphoid / pathology*
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Leukemia, Myeloid / metabolism*
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Mice
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphorylation / drug effects
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Plant Extracts / pharmacology*
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Plasmacytoma / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Receptors, TNF-Related Apoptosis-Inducing Ligand / biosynthesis
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Transcription Factor CHOP / biosynthesis
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Viscum album / chemistry*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Amino Acid Chloromethyl Ketones
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Anthracenes
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DDIT3 protein, human
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Endoplasmic Reticulum Chaperone BiP
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Eukaryotic Initiation Factor-2
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Plant Extracts
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Proto-Oncogene Proteins c-bcl-2
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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Transcription Factor CHOP
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pyrazolanthrone
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Caspase 9
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Glutathione