Abstract
Eupatorin is a naturally occurring flavone that inhibits cell proliferation in human tumor cells. Here we demonstrate that eupatorin arrests cells at the G2-M phase of the cell cycle and induces apoptotic cell death involving activation of multiple caspases, mitochondrial release of cytochrome c and poly(ADP-ribose) polymerase cleavage in human leukemia cells. This flavonoid induced the phosphorylation of members of the mitogen-activated protein kinases and cell death was attenuated by inhibition of c-jun N-terminal kinases/stress activated protein kinases. Eupatorin-induced cell death is mediated by both the extrinsic and the intrinsic apoptotic pathways and through a mechanism dependent on reactive oxygen species generation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / drug effects*
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Caspases / genetics*
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Caspases / metabolism
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Cell Division / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cytochromes c / metabolism
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Flavonoids / pharmacology*
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G2 Phase Cell Cycle Checkpoints / drug effects
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Gene Expression Regulation, Neoplastic*
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HL-60 Cells
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Humans
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mitogen-Activated Protein Kinases / genetics*
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Mitogen-Activated Protein Kinases / metabolism
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Phosphorylation / drug effects
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Proteolysis / drug effects
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Reactive Oxygen Species / metabolism
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Signal Transduction
Substances
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Antineoplastic Agents, Phytogenic
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Flavonoids
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Reactive Oxygen Species
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eupatorin
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Cytochromes c
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Poly(ADP-ribose) Polymerases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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Caspases
Grants and funding
This work was supported by a grant (number: SAF2010-21380) from the Spanish Ministry of Science and Innovation and European Regional Development Fund (URL:
www.micinn.es). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.