The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in human leukemia cells (U937) through the mitochondrial rather than the receptor-mediated pathway.
Flavopiridol (FP), an inhibitor of cyclin dependent kinases 1, 2 and 4, potently induced apoptosis in U937 human monoblastic leukemia cells. This process was accompanied by characteristic morphological changes, inner mitochondrial membrane permeability transition, release of cytochrome c, processing of procaspases, and generation of reactive oxygen species. Significantly, the general caspase inhibitor Boc-FMK did not block the release of cytochrome c, whereas it did block cleavage of BID and the loss of Deltapsi(m). Neither FP-induced apoptosis nor cytochrome c release was inhibited by the pharmacological caspase-8 inhibitor IETD-FMK or endogenous expression of viral caspase-8 inhibitor CrmA. Finally, FP-mediated apoptosis, but not cytochrome c release, was partially blocked by the free radical scavenger LNAC. Collectively, these findings indicate that FP induces apoptosis in U937 cells via the release of cytochrome c from the mitochondria and independently of activation of procaspase-8.
Decker
R H
RH
Department of Medicine, Medical College of Virginia, Richmond, VA 23298, USA.
Dai
Y
Y
Grant
S
S
D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D020298:U937 Cells
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D005419:Flavonoids; D010545:Peroxides; D010880:Piperidines; D017382:Reactive Oxygen Species; C077990:alvocidib; D018844:Cyclin-Dependent Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases