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Experimental Therapeutics |
ura
Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan [Y. O., A. T., S. L., T. T.]; Kitasato Institute, Minato-ku, Tokyo 108-8642, Japan [S. .]; and Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo 170-8455, Japan [T. T.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(topo II), rendering cells resistant to topo
II-targeted drugs, such as etoposide and doxorubicin. We show here that
inhibition of proteasome attenuated drug resistance by inhibiting topo
II depletion induced by glucose starvation and hypoxia. topo
II restoration was seen only at the protein levels, indicating that
the topo II protein depletion occurred through a proteasome-mediated
degradation mechanism. The stress-induced etoposide resistance was
effectively prevented in vitro by the proteasome
inhibitor lactacystin in both intrinsically resistant and sensitive
tumor cells (colon cancer HT-29 and ovarian cancer A2780 cells,
respectively). Furthermore, lactacystin effectively enhanced the
antitumor activity of etoposide in the refractory HT-29 xenograft.
These results indicate that lactacystin could serve as a new
therapeutic agent to circumvent resistance to topo II-targeted
chemotherapy in solid tumors. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Inducible resistance has been shown to correlate with a stress response
of cells, which is referred to as the glucose-regulated stress response
(9, 10, 11, 12)
. This stress response is characterized by the
induction of the endoplasmic reticulum-resident stress proteins GRP78
and GRP94 (13)
. In in vitro studies, the
GRP-inducing conditions, including glucose starvation, hypoxia, and
treatment with related chemical stressors, have been shown to induce
resistance to multiple drugs, such as etoposide, doxorubicin,
camptothecin, and vincristine (9, 10, 11, 12)
. This type of drug
resistance is reversible and decays rapidly when stress conditions are
removed. The induction of drug resistance can be partly explained by
cell cycle arrest or delay at the G1 phase in
stressed cells (14
, 15) , because most anticancer drugs are
primarily effective against rapidly dividing cells. In addition,
multiple drug resistance could be associated with activation of NF-
B
under stress conditions (16
, 17)
, because recent evidence
shows that it plays a role for protecting cells against drug-induced
apoptosis in certain cell types (18
, 19)
but not in all
(20)
.
Specific mechanisms of resistance to certain types of drugs may
also be involved in inducing resistance. Previous studies have
demonstrated that stress conditions induce decreased expression of topo
II3
(3)
, an important target for a group of antitumor drugs
(11
, 21)
. topo II plays an essential role in regulating
the topological structure of DNA by breakage-reunion of double-stranded
DNA (22)
. topo II-directed antitumor drugs, such as
etoposide and doxorubicin, stabilize the cleavable complex, an
intermediate product of the topo II-catalyzed reaction
(23)
. Accumulation of the cleavable complexes is thought
to lead to eventual cell death, and a decrease in the number of
cleavable complexes could confer drug resistance (24, 25, 26)
.
Indeed, several cancer cell lines, isolated by multistep selection for
resistance to topo II poisons, show decreased topo II expression
(24, 25, 26)
. Thus, the stress-induced topo II depletion
may be a mechanism for the inducible cell resistance to topo
II-targeted drugs.
In this study, we focused on restoring the decreased topo II
expression to reverse the inducible resistance because a high-level
expression of topo II is essential for cell death induced by topo
II-directed drugs. We show here that the decrease in topo II
expression under glucose starvation and hypoxia was blocked by
selective inhibitors of proteasome, a major intracellular machinery for
protein degradation (27)
. The proteasome inhibitors
significantly restored the cellular sensitivity to topo II-targeted
drugs in vitro. We further evaluated the proteasome
inhibition against the in vivo resistance to the topo
II-targeted chemotherapy in a solid tumor model.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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For the synchronized culture, we trapped cells in M phase by treatment with 40 ng of nocodazole/ml (Wako Pure Chemical Industries, Osaka, Japan) for 9 h, collected by gentle pipetting, and replated in fresh medium glucose-free medium, or hypoxic conditions. The cell cycle distributions were determined using a Becton Dickinson fluorescence-activated cell analyzer (15) . For the colony formation assay, cells were treated for 1 or 4 h with etoposide and doxorubicin (generous gifts from Bristol-Myers Squibb and Kyowa Hakko, Tokyo, Japan, respectively) and seeded at appropriate dilutions in fresh medium. After 7–8 days, colonies were fixed with 10% formaldehyde, stained with 0.01% crystal violet, and counted. Lactacystin was prepared as described previously (29 , 30) . The proteasome inhibitors PSI, MG115, and MG132, as well as E64 and ZLLal, were from the Peptide Institute Inc. (Osaka, Japan). These compounds were dissolved in DMSO or distilled water (for E64) and added to culture medium so that the final concentration of DMSO was less than 0.5%. For in vivo treatment, lactacystin was dissolved in a saline solution. In the M phase synchronization system, the proteasome inhibitors, as well as other protease inhibitors, were added into the medium 1 h after nocodazole was removed, to avoid any effects on the release from M phase.
Immunoblot Analysis.
Whole cell lysates were prepared by solubilizing cells in 1x
SDS sample buffer (10% glycerol, 5% 2-mercaptoethanol, 2%
SDS, 62.5 mM Tris-HCl, pH 6.8), as described previously
(11)
. Equal amounts of proteins were subjected to SDS-PAGE
and electroblotted onto a nitrocellulose membrane (Schleicher &
Schuell, Dassel, Germany). Membranes were probed with mouse
monoclonal antibodies against human topo II (clone KF4; Cambridge
Research Biochemicals, Wilmington, DE) or human topo IIß (clone 8F8;
PharMingen, San Diego, CA). The specific signals were detected using an
enhanced chemiluminescence detection system (Amersham Pharmacia
Biotech, Tokyo, Japan).
Northern Blot Analysis.
mRNA was isolated using a QuickPrep Micro mRNA Purification
Kit (Amersham Pharmacia Biotech). The RNA samples (2 µg/lane) were
separated by 1% formaldehyde-agarose gel electrophoresis and blotted
onto a nylon membrane (Schleicher & Schuell). Membranes were
subsequently hybridized with a 32P-labeled human
topo II cDNA fragment (2998–4596) as a probe for topo II. The
equality of the loading mRNA was confirmed by hybridization with a
glyceraldehyde-3-phosphate dehydrogenase cDNA.
Cellular Accumulation of Antitumor Drugs.
Under normal or glucose starvation conditions, synchronized HT-29
cells, as above, were treated with lactacystin at 7.5 µM
or the vehicle for 15 h. During the last 4 h of treatment,
the cells were exposed to 5 µg of
[3H]etoposide/ml (0.5 µCi/ml; Moravek
Biochemicals Inc., Brea, CA) or 0.1 µg of
[14C]doxorubicin/ml (0.05 µCi/ml; Amersham
Pharmacia Biotech) by adding the drugs directly into the medium.
Immediately after drug treatment, the cells were washed three times
with ice-cold PBS and lysed with 400 µl of 0.4 N NaOH,
and the radioactivity was counted in 2 ml of Scintisol EX-H (Wako).
In Vivo Evaluation in Human Tumor Xenograft Model.
Tumors were established by s.c. injection of HT-29 cells (1 x 107) suspended in physiological saline
into the upper thighs of nude mice (Charles River Laboratories,
Yokohama, Japan). Therapeutic experiment (4 or 6 mice in each group)
were started (day 0) when tumors had grown to 100–200
mm3 (usually about 10 days after inoculation). In
the first experiment, etoposide and lactacystin were administrated i.p.
at doses of 33 and 40 mg/kg/day, respectively, on days 0, 4, and 8. In
the second experiment, etoposide and lactacystin were administrated
i.p. at doses of 33 and 25 mg/kg/day, respectively, on days 0, 2, and
4. The control group received physiological saline. Tumor volume was
determined by measuring three orthogonal diameters of each tumor and
calculated (D1 x D2 x D3). As an indicator of toxicity, we
calculated the maximum weight loss (% reduction of day 0) for
individual animals. The statistical significance of tumor growth (tumor
volume on each day minus tumor volume on day 0) between the groups was
evaluated using a one-way ANOVA with Dunnett’s test, for which
P < 0.05 was deemed significant using a
two-tailed test between the groups of single-treated and combined
treated mice.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Depletion through Glucose Starvation during
G1. expression and cell cycle arrest or delay at the
G1 phase. To clarify this relationship, we
determined the topo II protein levels in HT-29 cells that were
synchronized at M phase. After release from M phase, cells were
cultured for 12 h under normal or glucose starvation conditions.
The intracellular topo II level was reduced under glucose starvation
conditions to less than 20% that under normal conditions (Fig. 1A
, 0 µM lactacystin). As we have
reported previously (31)
, the normal level of topo II
was relatively constant during the culture period (data not shown).
Glucose starvation also caused cell cycle arrest or delay at the
G1 phase in the synchronization system (as shown
below in Fig. 5
), whereas the cell cycle synchronously progressed
through G1 to S under normal conditions (data not
shown; see Ref. 31
). These results demonstrate that topo
II depletion occurs during the prolonged G1
phase induced by glucose starvation. In contrast, the expression of
topo IIß did not change under glucose starvation conditions (data not
shown). In the following in vitro studies, we used the
synchronization system to examine the relationship between the
restoration of topo II expression and the cellular sensitivity to
topo II poisons.
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Depletion and Drug Resistance by
Proteasome Inhibition.
depletion induced by glucose starvation in a dose-dependent manner
(2.5–10 µM), as determined using the above synchronized
culture of HT-29 cells followed by immunoblotting (Fig. 1A)
.
However, lactacystin did not affect the topo II protein levels under
normal conditions. We also determined topo II mRNA expression using
Northern blot analysis (Fig. 1B)
. Glucose starvation reduced
the topo II mRNA levels; however, reduction still occurred in the
presence of lactacystin at 7.5 µM. Lactacystin
effected a small reduction in topo II mRNA expression under normal
conditions. Thus, lactacystin blocks the topo II depletion at a
posttranslational level, likely by inhibiting the proteasome-mediated
degradation of this enzyme.
HT-29 cells showed a strong resistance to etoposide under glucose
starvation conditions. The colony-forming ability of etoposide-treated
(10 µg/ml) cells was approximately 85% (set as 1 in Fig. 1C
) but less than 10% under normal conditions. This
etoposide resistance was significantly reduced when lactacystin was
added (Fig. 1C)
. Reduced etoposide resistance correlated
well with inhibition of topo II depletion by lactacystin (compare
A and C of Fig. 1
). Lactacystin alone showed weak
toxicity; for example, 7.5 µM lactacystin
reduced the colony-forming ability of HT-29 cells to 75–85% under
both glucose starvation and normal conditions (Fig. 1C
and
data not shown). This dose of lactacystin was effective against
resistance to various concentrations of etoposide, shifting the
concentration response curve to the left (Fig. 2A)
. In contrast, lactacystin had little effect under normal
conditions. Similar results were obtained with the topo II-targeted
drug doxorubicin (Fig. 2B)
. However, lactacystin had no
effect against the non-topo II-targeted drugs methotrexate and
vincristine (Fig. 2, C and D)
.
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depletion induced by glucose starvation at 5
µM and were effective at concentrations as low as 1
µM (Fig. 3A
and data not shown). In contrast, such inhibition of topo
II depletion was not seen with protease inhibitors E64 and ZLLal,
even at 50 µM. E64 inhibits cysteine proteases
but not proteasome (32)
, and ZLLal is a strong calpain
inhibitor with a related structure to MG132 (ZLLLal; Ref.
33
). In agreement with these findings, PSI, MG115, and
MG132 (2.5 µM each) significantly reduced
etoposide resistance, whereas E64 and ZLLal had little effect, even at
25 µM (Fig. 3B)
. Hypoxia, as well as
glucose starvation, caused the topo II depletion, and this was also
prevented by the proteasome inhibitors (Fig. 3C)
.
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depletion (Fig. 4)
. Lactacystin blocked topo II depletion at concentrations lower than
those in HT-29 cells (compare Figs. 4A
and 1A
).
Lactacystin at 5 µM alone, the concentration we
used for the combination with etoposide, reduced the colony-forming
ability of A2780 cells to 70 and 85% under normal and glucose
starvation conditions, respectively. This dose of lactacystin
significantly reduced the resistance of A2780 cells to etoposide (Fig. 4B)
. These results indicate that the proteasome inhibition
was effective against inducible etoposide resistance, despite the
intrinsic differences in drug sensitivity of different tumors or cell
types.
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. Fifteen h after release from M phase, HT-29 cells showed
G1 phase arrest or delay under glucose starvation
conditions but a synchronous progression through
G1 to S phase under normal conditions. The
proteasome inhibitors, PSI and lactacystin, had little effect on the
cell cycle; they suppressed neither G1 arrest or
delay in stressed cells nor progression from G1
to S phase in unstressed cells. We also determined the effect of
lactacystin on accumulation of etoposide and doxorubicin into HT-29
cells. Glucose starvation slightly reduced the accumulation of drugs
(0.17 ± 0.01 and 0.14 ± 0.01 ng of
etoposide/104 cells in control and stressed
cells, respectively, and 0.19 ± 0.01 and 0.18 ± 0.01 ng of doxorubicin/104 cells in
control and stressed cells, respectively). However, lactacystin did not
reverse the decreased accumulation under glucose starvation
(0.15 ± 0.01 ng of etoposide/104
cells and 0.18 ± 0.01 ng of
doxorubicin/104 cells), and it scarcely affected
drug accumulation under normal conditions (0.14 ± 0.01
ng of etoposide/104 cells and 0.17 ± 0.01 ng of doxorubicin/104 cells). We
concluded that lactacystin prevented inducible resistance to topo
II-targeted drugs without affecting the cell cycle delay or the drug
accumulation.
In Vivo Antitumor Activity of Etoposide with
Lactacystin.
We determined whether the proteasome inhibition would enhance the
antitumor activity of etoposide in HT-29 xenografts. For this purpose,
we used lactacystin because it is the most selective for proteasome
among the above-described inhibitors (34)
. In the first
experiment, mice (4 mice/group) were given etoposide (33 mg/kg),
lactacystin (40 mg/kg), or a combination of the two on days 0, 4, and
8, after tumor volumes reached 150–200 mm3. The
combination of etoposide and lactacystin showed a notable inhibition of
the tumor growth. However, there was an apparent weight loss in the
mice treated with lactacystin alone or the combination (data not
shown).
In the second experiment, we used a lower dose of lactacystin. Mice (6
mice/group) were administered etoposide at 33 mg/kg, lactacystin at 25
mg/kg, or a combination on days 0, 2, and 4, after the tumor volumes
reached about 100 mm3 (Fig. 6)
. Single-agent treatment with etoposide or lactacystin slightly
inhibited the growth of the HT-29 xenografts compared with control
treatment (saline). The tumor volumes were reduced to approximately
80% at day 12 with either agent alone. The combination of etoposide
and lactacystin effectively inhibited tumor growth, resulting in a
tumor volume of 43% of control at day 12. There were
significant differences in tumor growth between the combination
treatment and the single-treated groups from day 11 to day 16
(P < 0.05). There were no toxic deaths in
the single agent or the combination treatment. The weights of animals
treated with single agent etoposide or lactacystin decreased by an
average (± SE) of 17.8 ± 2.6 and 5.5 ± 1.1%, respectively. The maximum weight loss of mice given the
combination treatment was 12.9 ± 0.7%. Thus, etoposide
combined with the proteasome inhibitor lactacystin produced antitumor
activity superior to that of etoposide alone against the HT-29
xenografts without increasing the apparent toxicity.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(11
, 21) . This study shows that the proteasome inhibitors
restored topo II expression, thereby preventing inducible resistance
to etoposide and doxorubicin. Although topo II is a cell
cycle-regulated protein in untransformed cells, it often escapes the
regulation in exponentially growing tumor cells (31
, 35
, 36)
. The deranged expression of topo II may be partly
explained by a long protein half-life, about 27 h in HeLa cells
(37)
. In contrast, topo II levels decreased sharply
during the prolonged G1 phase under stress
conditions. Thus, expression of topo II is regulated differently in
the growing state than in the stressed state. In agreement with this
was the finding that proteasome inhibitors suppressed topo II
decrease in stressed cells but showed no effect in unstressed cells,
resulting in a selective augmentation of sensitivity to topo II poisons
under stress conditions.
The expression of topo II in vivo often shows marked
heterogeneity among tumor cells (38)
. It is likely that
the heterogeneity in topo II expression is generated, in part, by
glucose starvation and hypoxia within microregions of solid tumors. It
is important to note that such stress conditions are not necessarily
consistent because as blood vessels open and close they create
microregions of acute glucose starvation and hypoxia (39)
.
Dynamic changes in the microenvironment would provide opportunities for
preventing inducible resistance by proteasome inhibition. In keeping
with this idea, the proteasome inhibitor lactacystin effectively
enhanced antitumor activity of etoposide in the human cancer xenograft
model. Although the validity of the mechanism of action in
vivo remains to be established, the in vivo efficacy of
lactacystin emphasizes the potency of our in vitro system,
aimed at reversing inducible resistance to topo II poisons.
Proteasome plays a major role in intracellular protein degradation
(27
, 40 , 41)
. The proteasome-mediated proteolysis is
normally regulated by ubiquitination of the target proteins (40
, 41)
. topo II can be conjugated with polyubiquitin in a
cell-free system with extracts of cancer cells, indicating that a
ubiquitination pathway of topo II exists in cancer cells
(42)
. Thus, the ubiquitin-proteasome pathway seems to be
responsible for topo II degradation under stress conditions. As
observed by Nakajima et al. (42)
, however, such
topo II ubiquitination has been hardly detected in intact cells,
even in the presence of proteasome inhibitors. Although the reason is
unclear, one possibility is that topo II ubiquitination may occur
less rapidly than with the more easily detected cases, thereby giving
time for de-ubiquitinating enzymes (40
, 41)
to remove the
polyubiquitin chains in the presence of proteasome inhibitors.
Alternatively, although it seems less likely, proteasomes might lead to
activation of another, unidentified protease that degrades topo II.
Additional studies are needed to clarify the precise mechanisms of topo
II degradation mediated by proteasome under stress conditions.
The efficiency of proteasome-mediated protein degradation may be
affected not only by modification of target proteins but also by
changes in the intracellular distribution of proteasomes
(43)
. In a previous study, we found that proteasomes
accumulated in the nucleus under glucose starvation and hypoxic
conditions (44)
. Because topo II exists in the nucleus,
this accumulation could contribute to the efficient degradation of topo
II. In the same study, we showed that the nuclear proteasome
activity increased 3–4-fold in HT-29 cells under glucose starvation,
whereas the increase ratio was approximately 1.5 in A2780 cells
(44)
. This is consistent with our present finding that
higher concentrations of lactacystin were required to inhibit the topo
II degradation in HT-29 than in A2780 cells. These results would
provide another rationale for proteasome as a target to reverse
inducible resistance.
Inducible resistance to topo II poisons was not completely reversed by
the proteasome inhibitors, although the topo II expression recovered
completely. This residual resistance implied that the
proteasome-mediated mechanism was not the sole cause for the inducible
resistance. We showed that the proteasome inhibitors did not affect the
stress-induced G1 arrest or delay of the cell
cycle. The cytotoxicity of topo II-targeted drugs is thought to be
derived from double-strand breaks in DNA, which are produced by a
collision of the drug-stabilized topo II-DNA cleavable complex with the
DNA replication fork and/or the transcription complex
(23, 24, 25, 26)
. Therefore, the residual resistance seemed to be
associated with a reduction in DNA synthesis induced by the
G1 arrest or delay. Supporting this was the
finding that lactacystin had little effect on stress-induced resistance
to the non-topo II-targeted drugs methotrexate and vincristine, which
are less active against G1 phase cells (Fig. 2, C and D)
.
In conclusion, this study indicates that the proteasome inhibitor lactacystin may be useful for improving the efficacy of topo II-targeted chemotherapy against solid tumors. Because physiological stress conditions, such as glucose starvation and hypoxia, are common features of solid tumors, our results may apply to diverse solid tumors, those intrinsically sensitive and resistant to topo II-targeted drugs. Recently, proteasome inhibition, by itself, has been attempted as a new approach in cancer chemotherapy. In fact, a newly developed inhibitor, PS-341, has growth-inhibitory activity for a broad range of cell lines and has antitumor activity, in solid tumor models, in a sensitive cell line to the drug (45) . Thus, proteasome inhibition itself may have a therapeutic potential. With these studies, our present results demonstrate that proteasome inhibitors show a promise for the treatment of solid tumors.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported in part by a special
grant for Advanced Research on Cancer; a Grant-in-Aid for Cancer
Research from the Ministry of Education, Science, Sports and Culture of
Japan; and the Vehicle Racing Commemorative Foundation. 
2 To whom requests for reprints should be
addressed, at Laboratory of Biomedical Research, Institute of Molecular
and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku,
Tokyo 113-0032, Japan. Phone: 81-3-5841-8488; Fax: 81-3-5841-8487;
E-mail: ttsuruo{at}imcbns.iam.u-tokyo.ac.jp
3 The abbreviations used are: topo II, DNA
topoisomerase II; PSI,
carbobenzoxy-L-isoleucyl-
-t-butyl-L-glutamyl-L-alanyl-L-leucinal;
MG115,
carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal;
MG132,
carbobenzoxy-L-leucyl-L-leucyl-L-leucinal;
ZLLal, carbobenzoxy-L-leucyl-L-leucinal.
Received 9/ 7/99. Accepted 2/29/00.
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N. E. Matthews, M. A. Adams, L. R. Maxwell, T. E. Gofton, and C. H. Graham Nitric Oxide-Mediated Regulation of Chemosensitivity in Cancer Cells J Natl Cancer Inst, December 19, 2001; 93(24): 1879 - 1885. [Abstract] [Full Text] [PDF]
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 L. M. Brandes, Z. P. Lin, S. R. Patierno, and K. A. Kennedy Reversal of Physiological Stress-Induced Resistance to Topoisomerase II Inhibitors Using an Inducible Phosphorylation Site-Deficient Mutant of Ikappa Balpha Mol. Pharmacol., September 1, 2001; 60(3): 559 - 567. [Abstract] [Full Text] [PDF]
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 J. A. Vrana and S. Grant Synergistic induction of apoptosis in human leukemia cells (U937) exposed to bryostatin 1 and the proteasome inhibitor lactacystin involves dysregulation of the PKC/MAPK cascade Blood, April 1, 2001; 97(7): 2105 - 2114. [Abstract] [Full Text] [PDF]
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and •) or glucose starvation conditions
(
and 
). The proteasome inhibitor lactacystin at 7.5
µM (• and 
