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Vol. 61, Issue 6, 1313-1321, June 2002
Departments of Medicine (L.C., Y.D., M.R., R.R., J.A., S.G.),
Pharmacology and Toxicology (P.D., S.G.), Radiation Oncology (R.S.,
P.D., S.G.), and Microbiology (S.G.), Virginia Commonwealth University,
Medical College of Virginia, Richmond, Virginia
Previous studies have shown that coexposure to marginally toxic
concentrations of phorbol 12-myristate 13-acetate (PMA; 10 nM) and the
cyclin-dependent kinase inhibitor flavopiridol (FP; 100-200 nM)
synergistically induces apoptosis in human myeloid leukemia cells U937
and HL-60 (i.e., >50% apoptotic at 24 h). Attempts have now been
made to characterize the cell death pathway(s) involved in this
phenomenon. In contrast to cytochrome c release and
caspase-3 activation, which occur within 2.5 h of PMA/FP
coexposure, caspase-8 activation and Bid cleavage appeared as later
events. Such findings implicate the mitochondria-dependent pathway in the initial induction of apoptosis by PMA/FP. However, U937 cells ectopically expressing CrmA, dominant-negative caspase-8, or
dominant-negative Fas-associated death domain that were highly
resistant to tumor necrosis factor (TNF)/cycloheximide-induced
lethality displayed significant, albeit incomplete, resistance to
PMA/FP-induced apoptosis after 24 h. Furthermore, coadministration
of TNF soluble receptor significantly attenuated PMA/FP-induced
apoptosis in U937 (p < 0.02) and HL-60
(p < 0.03) cells at 24 h. PMA/FP
coadministration also triggered substantial increases in TNF
mRNA
and protein secretion compared with the effects of PMA administered
alone. The protein kinase C (PKC) inhibitor bisindolylmaleimide (1 µM) completely blocked PMA/FP-induced TNF secretion in U937 cells and attenuated apoptosis. Taken together, these results suggest that
coadministration of PMA with FP in myeloid leukemia cells initially
triggers mitochondrial damage, an event followed by the PKC-dependent
induction and release of TNF, supporting a model in which the
synergistic induction of leukemic cell apoptosis by this drug
combination proceeds via both mitochondrial- and TNF receptor-related
apoptotic pathways.
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