Journal
CELL DEATH AND DIFFERENTIATION
Volume 8, Issue 7, Pages 715-724Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4400868
Keywords
flavopiridol; apoptosis; leukemia; caspase; cytochrome c
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Funding
- NCI NIH HHS [CA83705, CA63753] Funding Source: Medline
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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 BlD and the loss of Delta Psi (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.
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