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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.
 |
Abstract |
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.
(Blood. 2000;96:393-397)
© 2000 by The American Society of Hematology.
| |
Introduction |
Chronic lymphocytic leukemia (CLL) is
presently an incurable disease, representing the most common form of
leukemia in North America and Europe.1 These malignant
cells are most commonly comprised of CD5+ mature
B-lymphocytes that gradually accumulate in the patient because of
defective programmed cell death rather than accelerated cell
division.2 The underlying defect in apoptosis in B-cell CLL
(B-CLL) is undefined, but most cases express the antiapoptotic protein
Bcl-2 at high levels.3 Higher levels of Bcl-2 or increased ratios of Bcl-2 relative to its proapoptotic antagonist Bax have been
correlated with refractory disease, disease progression, and shorter
survival.4-8 Higher levels of the antiapoptotic protein Mcl-1 have also been correlated with failure to achieve complete remission in patients treated with alkylating agents or purine nucleosides.9 The underlying defect in programmed cell
death in B-CLL cells presumably accounts for the general
chemoresistance of this disease. Although more than half of patients
respond initially to single agent therapy, B-CLL cells almost uniformly
progress to refractory disease given sufficient time.10,11
Thus, a need exists for novel agents that can overcome blocks to
apoptosis in B-CLL, particularly in treatment of refractory patients.
Flavopiridol and 7 hydroxy-staurosporine (UCN-01) are small molecule
compounds that inhibit selected protein kinases by interacting with
their adenosine triphosphate (ATP)-binding sites. Flavopiridol is a
novel semisynthetic flavone derivative of the alkaloid
rohitukine, originally identified as a cyclin-dependent kinase
inhibitor.12 UCN-01 is a derivative of the nonselective
protein kinase inhibitor staurosporine, which may have selective
inhibitory activity against protein kinase (PK) C family members at low
concentrations but which is probably capable of inhibiting a wide
variety of protein kinases.13 Both of these agents are
presently undergoing clinical evaluation for the treatment of a variety
of cancers, including B-cell malignancies.11 These agents
have been shown to induce apoptosis of B-CLL cells in vitro (reviewed
in Byrd et al11), but the mechanisms responsible are
unclear. Here, we demonstrate that flavopiridol and UCN-01 potently
down-regulate the levels of several antiapoptosis proteins in B-CLLs at
doses estimated to be within or near the range tolerated in vivo.
| |
Patients, materials, and methods |
Kinase inhibitors
Flavopiridol and UCN-01 were obtained from the Developmental
Therapeutics Branch of the National Cancer Institute (E. Sausville) with permission from Hochest Marion Roussel, Inc, and Kyowa Hakko Kogyo
Co, respectively. Flavopiridol was dissolved in dimethyl sulfoxide
(DMSO) at 1 mmol/L and stored at room temperature.
UCN-01 was dissolved in DMSO at 10 mmol/L and stored at
 20°C.
Patient specimens
Heparinized peripheral blood was obtained from both untreated
(n = 30) and previously treated (n = 19) patients diagnosed with
CD5+ B-CLL according to standard criteria.14 Of
the 49 specimens evaluated, 12, 17, 12, and 8 were derived from
patients with Rai stage 0, 1, 2, and 3 disease, respectively.
Lymphocytes were isolated by ficoll density-gradient
centrifugation9 and verified by immunofluroescence flow
cytometry to be composed of more than 95% CD5+
CD19+ B-cells. Except for some Rai 0 stage patients, B-CLL
cells represented more than 95% of the isolated lymphocytes, based on
flow-cytometric analysis.
Cell culture and apoptosis assays
B-CLL cells were cultured at 2 × 106 per
mL in Iscove's Modified Dulbecco's Medium containing
20% fetal calf serum, 1 mmol/L L-glutamine, and antibiotics as
described.9 Various concentrations of flavopiridol or
UNC-01 were added at the initiation of cultures, with or without 100 µmol/L benzoylcarbonyl-valine-alanine-asparte-fluoro-methyl-ketone (zVAD-fmk) (Calbiochem-Novabiochem, San Diego, CA), and
cells were recovered by centrifugation at various times thereafter for evaluation of the percentage of apoptotic cells with the use of a
fluorescence-based DNA end-labeling (TUNEL) method with flow-cytometry analysis or were lysed in RIPA buffer (10 mmol/L Tris pH 7.4, 150 mmol/L NaCl, 1% Triton X-100, 1% deoxycholate, 0.1% sodium dodecyl
sulfate [SDS], 5 mmol/L EDTA plus protease inhibitors, including
phenyl-methyl sulfonyl fluoride, aprotinin, leupeptin benzamidine, and
pepstatin) for immunoblot analysis as described in detail
previously.9 Correlations with Rai stage and prior therapy
were made by analysis of variance methods.
Immunoblot analysis of apoptosis-regulatory proteins
Cell lysates were normalized for total protein content (25 µg) and
subjected to SDS-polyacrylamide gel electrophoresis (SDS-PAGE) (12%
gels) immunoblot assay.9,15 Primary antibodies
included polyclonal rabbit antisera specific for Bcl-2,
Mcl-1, Bax, and Bak16-18 and murine monoclonal antibodies
specific for BAG-1,19  -actin (Sigma
Immunochemicals), poly(adenosine
5'-diphosphate-ribose) polymerase
PARP20 (gift of N. A. Berger), and X-linked
inhibitor of apoptosis (XIAP) (Transduction
Laboratories, San Diego, CA). Immunodetection was
accomplished with the use of horseradish-peroxidase-conjugated secondary antibodies and an enhanced chemiluminescence (ECL) method (Amersham) involving exposure to x-ray film (Kodak XAR, Rochester, NY). Multiple reprobings of blots were achieved by the
MAD method.15 Data were quantified from
x-ray films by scanning densitometry by means of the National
Institutes of Health image 1.57 program and compared for untreated and
drug-treated specimens by paired t test. Correlations with Rai
stage and prior therapy were made by the Fisher exact test.
| |
Results |
Treatment of B-CLL cells with flavopiridol or UCN-01 in vitro
resulted in increased apoptosis in most specimens evaluated. Dose-response analysis performed for CLL specimens with
flavopiridol and UCN-01 revealed increases in the percentage of
TUNEL-positive B-CLLs beginning at concentrations of more than 0.01 µmol/L for flavopiridol and more than 0.1 µmol/L for UCN-01 (Figure
1). The cytotoxic actions of flavopiridol
and UCN-01 generally reached plateau or near plateau levels at 0.1 µmol/L and 1.0 µmol/L, respectively (Figure 1). Among the 49 B-CLL
specimens employed throughout the studies reported here, quantification
of flavopiridol and UCN-01 effects on apoptosis was performed by TUNEL
assay for 12 and 19 specimens, respectively (Figure 1B,D). Although the
percentage of leukemic cells undergoing spontaneous apoptosis during
cell culture varied among B-CLL specimens tested, 0.1 µmol/L
flavopiridol and 1 µmol/L UCN-01 induced at least 10% further
increases in the percentage of TUNEL-positive B-CLLs in 10 of
12 (83%) and in 17 of 19 (89%) B-CLL patient specimens tested,
respectively (Figure 1B,D).
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| Fig 1.
Flavopiridol and UCN-01 induce apoptosis of B-CLL cells
in vitro.
B-CLL cells were cultured in the presence or absence of flavopiridol
(panels A and B) or UCN-01 (panels C and D) at the concentrations
indicated. After 3 days, the percentage of apoptotic cells was
determined by fluorescence-activated cell sorter-based TUNEL assay.
Panels A and C show representative examples of dose-response data.
Panels B and D show compilation of data for B-CLL specimens tested,
contrasting the percentage of apoptosis that occurred in vitro during 2 days' culture in the absence or presence of kinase inhibitors
(flavopiridol, P < .005; UCN-01, P < .0005).
|
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Analysis of several apoptosis-regulatory proteins in B-CLLs by
immunoblotting revealed striking changes induced by flavopiridol and
UCN-01. As demonstrated by the representative immunoblots presented in
Figure 2, flavopiridol and UCN-01 induced
concentration-dependent reductions in the levels of the antiapoptosis
proteins Mcl-1, BAG-1, and XIAP without significantly affecting the
levels of -actin (control) or the proapoptotic proteins Bax and Bak.
The concentrations of kinase inhibitors required for down-regulation of
antiapoptotic proteins coincided roughly with the doses needed to
increase apoptosis (compare Figures 1 and 2). Less consistent reductions in the steady-state levels of Bcl-2 were also observed in
some B-CLLs (see below).
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| Fig 2.
Flavopiridol and UCN-01 down-regulate antiapoptotic
proteins.
Representative immunoblot data show down-regulation of antiapoptosis
proteins by kinase inhibitors. B-CLL cells were cultured with or
without 0.1 µmol/L flavopiridol or 1 µmol/L UCN-01 for 2 days.
Whole cell lysates were then prepared, normalized for protein content
(25 µg), and subjected to SDS-PAGE/immunoblot analysis with the use
of antibodies specific for Bcl-2, Mcl-1, Bax, Bak, BAG-1, XIAP, and
-actin with ECL-based detection. Data illustrate a representative
B-CLL sample and are derived from a single blot by means of the MAD
immunoblotting method. Note that B-CLLs express both long (BAG-1L) and
short (BAG-1) isoforms of
BAG-119 and that both
were down-regulated by kinase inhibitors.
|
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When B-CLLs were treated for 48 hours with 0.1 µmol/L
flavopiridol, reductions of greater than 80% in the steady-state
levels of Mcl-1 (n = 3; P < .0001), BAG-1 (n = 3;
P < .05), and XIAP (n = 5; P < .005) were
observed in all specimens tested (Figure 3,
top), whereas reductions of 50% or more in Bcl-2 protein levels were
observed in 3 (60%) of the 5 B-CLLs evaluated (P = .01). In
contrast, no significant changes were observed in the levels of
proapoptotic proteins Bax (n = 5) and Bak (n = 3) (Figure 3, top).
Indeed, along with -actin, these proapoptotic proteins served as
additional controls, verifying that equivalent amounts of total protein
were loaded for each sample.
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| Fig 3.
Comparison of effects of kinase inhibitors on
apoptosis-regulatory proteins in B-CLL.
B-CLLs were cultured for 2 days with or without (control) 0.1 µmol/L
flavopiridol or 1 µmol/L UCN-01. Immunoblot data were quantified by
scanning densitometry to obtain rough estimates of the relative amounts
of proteins. Data are expressed as a percentage relative to untreated
(control) B-CLLs after normalization for -actin. Bars indicate
mean.
|
|
Similarly, culturing B-CLLs with 1 µmol/L UCN-01 for 48 hours resulted in decreases of 90% or more in the steady-state levels of Mcl-1 in 11 of 13 (85%) specimens tested (P < .0001)
and in the levels of XIAP (P < .0001) and BAG-1
(P < .05) in all (n = 4) B-CLLs evaluated
(Figure 3, bottom). Bcl-2 protein levels were reduced by more than 50%
in 10 of 15 (67%) of B-CLLs cultured with UCN-01
(P < .0001), whereas Bax (n = 5) and Bak (n = 3)
protein levels were unchanged (Figure 3, bottom). No significant
correlations were observed between Rai stage or prior therapy and
the effects of kinase inhibitors on apoptosis or gene expression.
Time-course studies demonstrated that decreases in antiapoptosis
protein levels preceded apoptosis induced by flavopiridol. Figure
4 presents representative data for XIAP and
Mcl-1. Note that greater than 50% decreases in XIAP and Mcl-1 protein
levels were achieved in flavopiridol-treated B-CLL cells at times (3 to
6 hours) when little induction of apoptosis had occurred, as determined
by DNA fragmentation (TUNEL assay) (Figure 4A,B). In contrast to
flavopiridol, decreases in antiapoptosis protein levels in
UCN-01-treated B-CLL cells were slower, occurring almost concomitantly with apoptosis. (Figure 4C, D).
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| Fig 4.
Time-course of flavopiridol- and UCN-01-induced
decreases in XIAP and Mcl-1 protein levels.
B-CLL cells were cultured with (shaded symbols) or without (open
symbols) 0.1 µmol/L flavopiridol (panels A and B) or 1 µmol/L
UCN-01 (panels C and D). At various times, cells were recovered from
cultures, and either lysates were prepared for immunoblot analysis
(circles) with the use of antibodies specific for XIAP (panels A and C)
or Mcl-1 (panels B and D) and the data were expressed as a percentage
of untreated cells, or apoptosis was determined by TUNEL assay
(squares). Data are representative of results obtained from 3 consecutive B-CLL specimens.
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To explore whether the decreases in antiapoptosis proteins induced by
flavopiridol and UCN-01 are dependent on caspase activation, B-CLL
cells were cultured with the broad-spectrum irreversible caspase
inhibitor zVAD-fmk. Comparisons were made by immunoblot analysis of the
effects of flavopiridol and UCN-01 on levels of XIAP, Mcl-1, and BAG-1
in the presence and absence of zVAD-fmk (Figure
5). As a control, levels of a prominent
caspase substrate, PARP, were also examined to monitor the
disappearance of the approximately 110-kd PARP protein, which undergoes
cleavage by caspases to generate an approximately 85-kd proteolytic
fragment.21 As summarized in Figure 5, flavopiridol- and
UCN-01-induced cleavage of PARP was significantly inhibited by
zVAD-fmk. In contrast, flavopiridol-induced decreases in the
steady-state levels of XIAP and Mcl-1 were not significantly affected
by zVAD-fmk. However, the decline in BAG-1 levels induced by
flavopiridol was partially prevented by zVAD-fmk, implying that
reductions in the levels of this protein represent a postcaspase
activation event. Unlike flavopiridol, decreases in the steady-state
levels of XIAP, Mcl-1, and BAG-1 triggered by UCN-01 were largely
inhibited by zVAD-fmk, suggesting a caspase-dependent process. Levels
of Bax, Bak, and -actin were unaffected by zVAD-fmk, flavopiridol,
UCN-01, or combinations of these reagents during these experiments (not
shown).
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| Fig 5.
Effects of caspase inhibitor zVAD-fmk on changes in
apoptosis protein levels induced by flavopiridol and UCN-01 in B-CLL
cells.
B-CLL cells derived from 6 to 9 patients were cultured with (+) or
without () 100 µmol/L zVAD-fmk and either 0.1 µmol/L
flavopiridol (top) or 1 µmol/L UCN-01 (bottom). After 18 to 24 hours,
cell lysates were prepared, normalized for total protein content, and
analyzed by immunoblotting with the use of antibodies specific for
PARP, Mcl-1, XIAP, or Bag-1. Data were quantified by scanning
densitometry and expressed as a percentage relative to control:
untreated B-CLL cells. PARP data refer to loss of the full-length 110 kd protein, which undergoes caspase-mediated cleavage.
Data were compared by means of a paired t test (P
values shown). Bars indicate mean of data points.
|
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| |
Discussion |
Flavopiridol and UCN-01 potently and reproducibly down-regulated the
levels of several antiapoptotic proteins in B-CLL cells in vitro,
without modulating expression of the proapoptotic proteins Bax and Bak.
The apoptosis-regulatory proteins examined here contain representatives
from several classes of proteins. Bcl-2, Mcl-1, Bax, and Bak are all
members of the Bcl-2 family of apoptosis-regulating proteins (reviewed
in Reed22 and Kroemer23). The relative ratios
of antiapoptotic (Bcl-2 and Mcl-1) and proapoptotic (Bax and Bak) Bcl-2
family proteins determine the sensitivity or resistance of cells to a
broad variety of cell death stimuli, including most anticancer
drugs.24 Gene transfer-mediated overexpression of either
Bcl-2 or Mcl-1 has been reported to increase resistance to apoptosis
induction by chemotherapeutic drugs (reviewed in Reed24,25). Bcl-2 family proteins may have multiple
biochemical functions, including modulation of mitochondrial responses
to cellular damage induced by anticancer drugs (reviewed in
Reed26).
BAG-1, in contrast, is a regulator of the Hsp70 family of molecular
chaperones that confers resistance to a variety of stimuli that induce
apoptosis or that produce cellular stress.27 Recently, it
has been suggested that Hsp70 controls a distal apoptosis checkpoint downstream of Bcl-2.28 Moreover, the nuclear-targeted
longer isoforms of BAG-1 reportedly bind steroid hormone receptor
complexes; BAG-1 family protein interactions with glucocorticoid
receptors and retinoic acid receptors confer resistance to apoptosis
induction by these steroids.29,30
Finally, XIAP is a member of the inhibitor-of-apoptosis
(IAP) family of apoptosis suppressors that directly
binds to and inhibits selected members of the caspase family of cell
death proteases.31 Elevated expression of XIAP and other
IAP-family proteins has been reported to confer increased resistance to
apoptosis induced by multiple stimuli, including chemotherapeutic drugs
(reviewed in Deveraux et al32). However, because these
proteins directly inhibit caspases, they may be particularly important
for avoidance of apoptosis mechanisms employed by immune cells,
including caspase-activating members of the tumor necrosis-factor
family of cytokine receptors and caspase-activating granzymes used by
cytolytic T-cells for inducing apoptosis in target cells.
The protein kinase targets of flavopiridol and UCN-01 that are relevant
to apoptosis induction in B-CLLs remain to be identified. Given the
nonproliferative nature of B-CLL, it seems unlikely (though not
impossible) that cyclin-dependent kinases are the major targets in this
disease. Candidates, however, include PKC family members, PKA, and
Akt/PKB, which have all been associated with apoptosis suppression in
various cellular contexts. Whatever the kinase target(s), flavopiridol
appears to be approximately 1 log more potent than UCN-01 at
down-regulating the levels of apoptosis proteins in B-CLLs, at least in
vitro. Moreover, flavopiridol-induced decreases in XIAP and Mcl-1 were
caspase-independent, unlike UCN-01 where reductions in the levels of
these proteins represented a postcaspase activation event. Thus, these
kinase inhibitors induce apoptosis through different mechanisms in
B-CLL cells.
It remains to be determined what the molecular basis is for the
observed down-regulation of Bcl-2, Mcl-1, BAG-1, and XIAP protein
levels in B-CLLs treated with flavopiridol or UCN-01. Conceivably,
reduced production of these proteins owing to suppression of
transcription or translation could be involved, as well as accelerated
degradation of their messenger RNAs (mRNAs) or the proteins. Of these
antiapoptosis proteins, Bcl-2 was the most variable in the influence of
kinase inhibitors, which possibly could be due to its long half-life.
Upon cessation of Bcl-2 mRNA production, it is not uncommon for Bcl-2
protein to remain in cells for a day or longer (reviewed in
Reed33). In contrast, Mcl-1 is thought to be a short-lived
protein because of PEST motifs present within this
Bcl-2 family member.34 Likewise, BAG-1 contains a
ubiquitin-like domain that could provide a mechanism for its rapid
degradation.35 XIAP also appears to be a short-lived
protein (unpublished data). Again, however, because down-regulation of Mcl-1 and XIAP protein levels by flavopiridol and UCN-01 was
differentially affected by caspase inhibitors, it is clear that these
kinase inhibitors use alternative mechanisms for reducing the levels of
these particular apoptosis-suppressing proteins.
In summary, we have observed that flavopiridol directly, and UCN-01
indirectly, down-regulate the levels of several antiapoptotic proteins
in B-CLLs in vitro. The reductions in antiapoptotic proteins induced by
UCN-01, however, appear to occur as a result of caspase activation,
presumably after commitment to apoptosis. In contrast, flavopiridol-induced decreases in XIAP and Mcl-1 precede apoptosis and
occur independently of caspase activation. Consequently,
flavopiridol-induced down-regulation of these survival proteins should
render B-CLLs more vulnerable to apoptosis induced by a variety of
stimuli, including cytotoxic anticancer drugs, glucocorticoids, and
immune-mediated attack. Further preclinical and clinical evaluation of
flavopiridol, UCN-01, and other kinase inhibitors in B-CLL is warranted.
| |
Acknowledgments |
The authors thank Ed Sausville (National Cancer Institute), Hochest
Marion Roussel, and Kyowa Hakko Kogyo for kinase inhibitors; N. A. Berger for anti-PARP antibody; and S. Farrar, R. Cornell, T. Brown, E. Smith, and A. Majors for manuscript preparation.
| |
Footnotes |
Submitted September 20, 1999; accepted March 8, 2000.
Supported by National Institutes of Health grants CA-55164, CA67329,
CA69381, AG15402, and CA81534. J.M.Z. is a Lymphoma
Research Foundation Fellow.
Reprints: John C. Reed, The Burnham Institute, 10901 North
Torrey Pines Rd, La Jolla, CA 92037; e-mail: jreed{at}burnham-inst.org.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction