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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-03-0940.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3333-3343
NEOPLASIA
Combined treatment with the checkpoint abrogator UCN-01 and
MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and
-resistant myeloma cells through an IL-6-independent
mechanism
Yun Dai,
Terry H. Landowski,
Steven T. Rosen,
Paul Dent, and
Steven Grant
From the Division of Hematology/Oncology,
Department of Radiation Oncology, Medical College of Virginia, Virginia
Commonwealth University, Richmond, VA; the University of Arizona School
of Medicine, Tucson, AZ; and the Robert Lurie Comprehensive Cancer
Center, Chicago, IL.
The effects of combined exposure to the checkpoint abrogator UCN-01
and pharmacologic MEK1/2 inhibitors were examined in human multiple
myeloma (MM) cell lines. Treatment of RPMI8226, NCI-H929, and U266 MM
cells with a minimally toxic concentration of UCN-01 (150 nM) for 24 hours resulted in mitogen-activated protein (MAP) kinase
activation, an effect that was blocked by coadministration of the
MEK1/2 inhibitor PD184352. These events were accompanied by enhanced
activation of p34cdc2 and a marked increase in
mitochondrial damage (loss of   m; cytochrome c and Smac/DIABLO
(direct IAP binding protein with low pI) release), poly(ADP-ribose) polymerase (PARP) cleavage, and apoptosis.
PD184352/UCN-01 also dramatically reduced clonogenic survival in each
of the MM cell lines. In contrast to As203,
apoptosis induced by PD184352/UCN-01 was not blocked by the
free-radical scavenger N-acetyl-L-cysteine. Whereas exogenous interleukin 6 substantially prevented
dexamethasone-induced lethality in MM cells, it was unable to protect
them from PD184352/UCN-01-induced apoptosis despite enhancing Akt
activation. Insulinlike growth factor 1 (IGF-1) also failed to
diminish apoptosis induced by this drug regimen. MM cell lines selected
for a high degree of resistance to doxorubicin, melphalan, or
dexamethasone, or displaying resistance secondary to
fibronectin-mediated adherence, remained fully sensitive to
PD184352/UCN-01-induced cell death. Finally, primary
CD138+ MM cells were also susceptible to UCN-01/MEK
inhibitor-mediated apoptosis. Together, these findings suggest that
simultaneous disruption of cell cycle and MEK/MAP kinase signaling
pathways provides a potent stimulus for mitochondrial damage and
apoptosis in MM cells, and also indicate that this strategy bypasses
the block to cell death conferred by several other well-described resistance mechanisms.
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