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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 393-397
PLENARY PAPER
Protein kinase inhibitors flavopiridol and
7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell
chronic lymphocytic leukemia
Shinichi Kitada,
Juan M. Zapata,
Michael Andreeff, and
John C. Reed
From the Burnham Institute, Program on Apoptosis and Cell Death
Research, La Jolla, CA, and the M. D. Anderson Cancer Center, Section
of Molecular Hematology and Therapy, Houston, TX.
Compounds that inhibit protein kinases are currently undergoing
clinical evaluation for the treatment of a variety of malignancies. The
kinase inhibitors flavopiridol and 7 hydroxy-staurosporine (UCN-01)
were examined for their effects on B-cell chronic lymphocytic leukemia
(B-CLL) cells in vitro (n = 49). Flavopiridol and UCN-01 induced
concentration-dependent apoptosis of most B-CLL samples tested, with
greater than 50% cell killing occurring at concentrations of less than
1 µmol/L, and with flavopiridol displaying more
potent activity than UCN-01. Flavopiridol (0.1 µmol/L) and UCN-01 (1 µmol/L) also induced striking decreases in the levels of the
antiapoptosis proteins Mcl-1, X-linked inhibitor of apoptosis
(XIAP), and BAG-1 in nearly all cases of B-CLL and of
Bcl-2 in approximately half of B-CLL specimens evaluated. In contrast,
expression of the proapoptotic proteins Bax and Bak was not
significantly influenced by these kinase inhibitors.
Flavopiridol-induced decreases in the levels of antiapoptosis proteins
Mcl-1 and XIAP preceded apoptosis and were not substantially affected
by the addition of caspase inhibitors to cultures. In contrast,
UCN-01-stimulated decreases in antiapoptosis proteins were slower,
occurred concurrently with apoptosis, and were partially prevented by
caspase inhibitors. The findings suggest that flavopiridol and UCN-01
induce apoptosis of B-CLL cells through different mechanisms. The
potent apoptotic activities of flavopiridol and UCN-01 against cultured
B-CLL cells suggest that they may be effective as single agents in the
treatment of B-CLL or for sensitizing B-CLL cells to conventional
cytotoxic drugs.
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