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Prepublished online as a Blood First Edition Paper on May 8, 2003; DOI 10.1182/blood-2002-12-3785.
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Blood, 1 September 2003, Vol. 102, No. 5, pp. 1824-1832
NEOPLASIA
Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways
Wentao Jia,
Chunrong Yu,
Mohamed Rahmani,
Geoffrey Krystal,
Edward A. Sausville,
Paul Dent, and
Steven Grant
From the Departments of Medicine, Biochemistry, Pharmacology, and
Radiation Oncology, Virginia Commonwealth University, Medical College of
Virginia, Richmond; and Developmental Therapeutics Program, National Cancer
Institute, Bethesda, MD.
Interactions between the protein kinase C (PKC) and Chk1 inhibitor UCN-01
and the heat shock protein 90 (Hsp90) antagonist 17-AAG have been examined in
human leukemia cells in relation to effects on signal transduction pathways
and apoptosis. Simultaneous exposure (30 hours) of U937 monocytic leukemia
cells to minimally toxic concentrations of 17-AAG (eg, 400 nM) and UCN-01 (eg,
75 nM) triggered a pronounced increase in mitochondrial injury (ie, loss of
mitochondrial membrane potential [  m]; cytosolic release
of cytochrome c), caspase activation, and apoptosis. Synergistic
induction of apoptosis was also observed in other human leukemia cell types
(eg, Jurkat, NB4). Coexposure of human leukemia cells to 17-AAG and the PKC
inhibitor bisindolylmaleimide (GFX) did not result in enhanced lethality,
arguing against the possibility that the PKC inhibitory actions of UCN-01 are
responsible for synergistic interactions. The enhanced cytotoxicity of this
combination was associated with diminished Akt activation and marked
down-regulation of Raf-1, MEK1/2, and mitogen-activated protein kinase (MAPK).
Coadministration of 17-AAG and UCN-01 did not modify expression of Hsp90,
Hsp27, phospho-JNK, or phospho-p38 MAPK, but was associated with further
p34cdc2 dephosphorylation and diminished expression of Bcl-2,
Mcl-1, and XIAP. In addition, inducible expression of both a constitutively
active MEK1/2 or myristolated Akt construct, which overcame inhibition of ERK
and Akt activation, respectively, significantly attenuated
17-AAG/UCN-01–mediated lethality. Together, these findings indicate that
the Hsp90 antagonist 17-AAG potentiates UCN-01 cytotoxicity in a variety of
human leukemia cell types and suggest that interference with both the Akt and
Raf-1/MEK/MAP kinase cytoprotective signaling pathways contribute to this
phenomenon.
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