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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-09-2739.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3648-3657
NEOPLASIA
Induction of tumor necrosis factor by bryostatin 1 is involved in
synergistic interactions with paclitaxel in human myeloid leukemia
cells
Shujie Wang,
Zhiliang Wang,
Paul Dent, and
Steven Grant
From the Department of Biochemistry, Division of
Hematology/Oncology, Department of Medicine, and Department of
Radiation Oncology, Virginia Commonwealth University/Medical College of
Virginia, Richmond.
Interactions between the protein kinase C (PKC)
activator/down-regulator bryostatin 1 and paclitaxel have been examined
in human myeloid leukemia cells (U937) and in highly
paclitaxel-resistant cells ectopically expressing a Bcl-2
phosphorylation loop-deleted protein ( Bcl-2). Treatment (24 hours)
of wild-type cells with paclitaxel (eg, 5 to 20 nM) in combination with
10 nM bryostatin 1 induced a marked increase in mitochondrial damage
(eg, cytochrome c and Smac/DIABLO [second
mitochondria-derived activator of caspases/direct IAP binding protein
with low pI] release), caspase activation, Bid cleavage, and
apoptosis; moreover, bryostatin 1 circumvented the block to
paclitaxel-induced mitochondrial injury and apoptosis conferred by
ectopic expression of the loop-deleted protein. Coadministration of
tumor necrosis factor (TNF) soluble receptors, or ectopic expression of
CrmA or dominant-negative caspase-8, abrogated potentiation of
paclitaxel-induced mitochondrial injury and apoptosis by bryostatin 1, implicating the extrinsic apoptotic pathway in this process. Similar
events occurred in HL-60 leukemia cells. Potentiation of
paclitaxel-induced apoptosis in wild-type and mutant cells by
bryostatin 1 was associated with increases in TNF- mRNA and protein
and was mimicked by exogenous TNF-. Coadministration of the
selective PKC inhibitor GFX (1 µM) blocked the increase in TNF-
mRNA levels and apoptosis in bryostatin 1/paclitaxel-treated cells.
Lastly, synchronization of cells in G2M increased their sensitivity to TNF--associated lethality. Collectively, these findings indicate that in U937 cells, bryostatin 1 promotes
paclitaxel-mediated mitochondrial injury and apoptosis, and circumvents
resistance to cell death conferred by loss of the Bcl-2 phosphorylation
domain, through the PKC-dependent induction of TNF-. They further
suggest that this process is amplified by paclitaxel-mediated arrest of cells in G2M, where they are more susceptible to
TNF--induced lethality.
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