Eupatorin-induced cell death in human leukemia cells is dependent on caspases and activates the mitogen-activated protein kinase pathway.
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.
Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
Sara
S
Estévez
Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
María Teresa
MT
Marrero
Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
José
J
Quintana
Department of Biochemistry and Molecular Biology, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
Francisco
F
Estévez
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D017382:Reactive Oxygen Species; C103110:eupatorin; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases