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Experimental Therapeutics, Preclinical Pharmacology |
Departments of Experimental Radiation Oncology [C. P., S. P., L. M., P. J. T.] and Neurosurgery [F. F. L., P. J. T.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although inhibitors of COX-1 and COX-2 have received considerable attention in cancer chemoprevention studies (13, 14, 15, 16) , there are also data from several experimental models indicating that these agents can also have antitumor activity. The NSAIDs sulindac, indomethacin, and ibuprofen, which are nonselective inhibitors of both COX-1 and COX-2, have been reported to reduce the proliferation rate of tumor cell lines grown in vitro and in vivo (17, 18, 19) . In addition, there is also evidence suggesting that NSAIDs can act as radiosensitizing agents. Milas et al. (20) and Furuta et al. (21) have shown that indomethacin enhances the antitumor efficacy of ionizing radiation against PG-producing, transplanted murine sarcomas. More recently, ibuprofen has been shown to enhance the radiosensitivity of human prostate carcinoma cells grown in vitro and as xenografts in immunodeficient mice (17 , 22) . However, because standard NSAIDs are nonselective in their inhibition, affecting both COX-1 and COX-2, treatment with these agents is limited by normal tissue toxicity. Of particular sensitivity is the gastrointestinal tract, which is especially dependent on COX-1 for normal function (23 , 24) . Therefore, because it is COX-2 that is overexpressed in many tumor types, the recently developed selective COX-2 inhibitors may be more amenable for use in antineoplastic therapy both alone and in combination with radiation. In support of this concept, we recently reported that SC-236, a selective COX-2 inhibitor, caused a dramatic enhancement of the in vivo radiation response of NFSA (25) and FSA murine sarcomas (26) . In contrast, the inhibitor had no influence on normal tissue damage by radiation.
The mechanism responsible for the enhanced tumor radioresponse induced by the COX-2 inhibitor has not been defined. Data from a murine model indicate that SC-236 can have an antiangiogenic effect (25) . However, because PGs have been shown to have radioprotective properties (27) , it is also possible that the inhibition of COX-2 may influence the intrinsic radiosensitivity of tumor cells. To investigate the effects of SC-236 on the intrinsic radiosensitivity of human tumor cells, we have performed a series of studies using the glioblastoma cell line U251. In addition to determining the effects of this COX-2 inhibitor on the intrinsic radioresponse of tumor cells, this cell line was also used as a means of exploring the potential for applying such compounds in combination with radiation for brain tumor treatment. Although treatment for a wide variety of human tumors could potentially improve with the use of a relatively nontoxic, selective radiosensitizer, particular benefits may be obtained for gliomas. Radiation is a major treatment modality for brain tumors in general, and despite the use of all available therapy, the median survival time for patients with glioblastoma multiforme, which accounts for the majority of human brain tumors, is only 1–2 years (28) . With respect to COX-2, there is a low level of constitutive expression in the CNS that seems to be localized in specific neuronal populations and not in glial cells (29) . Although COX-2 expression in gliomas has not yet been systematically compared with its expression in their normal glial counterparts, brain tumors have been reported to contain elevated levels of PGs (5) . We now report on the in vitro and in vivo effects of the selective COX-2 inhibitor SC-236 alone and in combination with radiation on U251 glioblastoma cells.
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MATERIALS AND METHODS |
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Cell Survival Analysis.
Cells in monolayer culture were exposed to 50 µM SC-236
(Searle, Skokie, IL) or vehicle (100% ethanol) for 24 or 48 h and
irradiated with graded doses of 
-rays using a
137Cs source (3.7 Gy/min). Cells that remained
attached were removed from the culture flask by exposure to 0.05%
trypsin/1 mM EDTA solution and replated in specified
numbers into 60-mm dishes in drug-free media for determination of
colony-forming ability. After 10 days of incubation, the contents of
the dishes were stained with 0.5% crystal violet in absolute methanol,
and colonies with >50 cells were determined. Radiation survival curves
were constructed after normalization for the cytotoxicity induced by
the drug alone. Survival curves were generated by combining data from
three to four independent experiments and fitting the average survival
levels by least squares regression using the linear quadratic model
(30)
.
Cell Cycle Phase Analysis.
Evaluation of cell cycle phase distribution was performed at the FCM
core facility at The University of Texas M. D. Anderson Cancer Center.
The treatment protocols were essentially the same as in the clonogenic
survival experiments. All of the cultures were subconfluent at the time
of collection. Cultures were collected for fixation with ice-cold 70%
ethanol, stained with propidium iodide, and analyzed using FCM as
described previously (31)
. Attached cells (those remaining
adhered to the dish) and floating cells (those having detached from the
monolayer) were stained separately in some experiments.
Apoptosis Assay.
The TUNEL assay (APO-DIRECT, PharMingen, San Diego, CA) was performed
according to the manufacturer’s instructions and analyzed basically as
described by Gonczyca et al. (32)
. Briefly,
fixed cells were washed in PBS, suspended in 50.75 µl of TdT buffer
with 0.75 µl of TdT enzyme and 8.0 µl of FITC-dUTP. After overnight
incubation at room temperature, cells were rinsed in buffer twice and
resuspended in 1 ml of propidium iodide/RNase A solution. After
incubating the cells in the dark for 30 min at room temperature, the
specimens were analyzed using FCM.
In Vivo Growth Delay Assay.
Tumors were generated by injecting 5 x 106
U251 cells s.c. into the right thighs of 4-month-old
nu/nu NCR mice. When tumors grew to 5 mm in diameter,
the mice were given SC-236 or vehicle in drinking water for 10
consecutive days. SC-236 was dissolved in a stock solution of 5% Tween
20 and 95% polyethylene glycol and diluted in distilled water to
achieve a final SC-236 concentration of 0.045 mg/ml. The mice drank
approximately 4 ml/day, which corresponded to an SC-236 dose of 6 mg/kg
body weight per day. Control animals received drinking water with
vehicle only. The water bottles were changed every 3 days. When tumors
grew to 7 mm in diameter, they were exposed to a 10-Gy single dose of
-radiation using a 60Co irradiator. To obtain
tumor growth curves, three mutually orthogonal diameters of tumors were
measured daily with a vernier caliper, and the mean values were
calculated. Regrowth of tumors was followed until tumor diameter
reached approximately 14 mm. Tumor growth delay was expressed as the
time in days for tumors in the treated groups to grow from 7 to 12 mm
in diameter minus the time in days for tumors in the control group to
reach the same size. Four experimental arms were studied:
(a) animals receiving vehicle only (controls);
(b) animals receiving SC-236 alone; (c) animals
receiving a single 10-Gy dose of radiation alone; and (d)
animals receiving a combination of SC-236 and single dose of 10-Gy
irradiation. The groups consisted of 7 to 10 mice each.
Northern Blotting.
Total RNA was isolated from cell monolayers using RNAzol (CINNA/Biotex
Laboratories, Friendswood, TX) according to the manufacturer’s
instructions. RNA samples (30 µg/lane) were separated on a 1%
agarose-formaldehyde gel and blotted onto Zeta-Probe GT genomic
membranes (Bio-Rad Laboratories, Hercules, CA). A human cDNA COX-2
probe was obtained from Oxford Biomedical Research (Oxford, MI).
Membranes were hybridized with 32P-cDNA probes by
random primer extension (Boehringer Mannheim, Indianapolis, IN) in
Hybrizol (Oncor Inc., Gaithersburg, MD) at 42°C and washed twice in
2x SSPE (300 mM sodium chloride, 200 mM sodium
phosphate, and 200 mM EDTA) and 0.1% SDS at room
temperature, once in 0.2% SSPE and 0.1% SDS at room temperature, and
once in 0.1x SSPE at 42°C. Visualization and quantification of mRNA
levels were performed using a Phosphor-Imager (Molecular Dynamics,
Sunnyvale, CA).
Western Blotting.
Cells from in vitro samples were washed twice with ice-cold
PBS, scraped in ice-cold PBS, and collected as whole cell lysates,
which were centrifuged at 14,000 rpm for 10 min at 4°C. For in
vivo tumor samples, fresh nonnecrotic tumor tissue was homogenized
using a glass-on-glass tissue homogenizer, thawed in ice-cold lysis
buffer [50 mM HEPES (pH 7.9), 0.4 M NaCl, 1
mM EDTA, 1 mM EGTA, 1
mM DTT, 0.5 mM
phenylmethylsulfonyl fluoride, 2 µg/ml aprotinin, 2 µg/ml
leupeptin, 5 µg/ml benzamidine, and 1% NP40], and incubated on ice
for 30 min. The protein concentration of the supernatant in each sample
was determined using the Bio-Rad Kit (Bio-Rad Laboratories) according
to the manufacturer’s instructions. A total of 60 µg of the
supernatant was resolved by SDS-PAGE. After electrophoresis, the
proteins were electroblotted onto an Immobilon-P membrane (Amersham
Corp., Arlington Heights, IL) and blocked at room temperature for
5 h using TBS-T (Tris-buffered saline and 5% nonfat milk in 0.1%
Tween 20). The membrane was probed with COX-2 polyclonal antibody
(Oxford Biomedical Research) in the blocking mixture overnight at
4°C. The membrane was washed in TBS-T and incubated for 40 min with
antirabbit IgG horseradish peroxidase-conjugated secondary antibody at
a 1:2000 dilution in the blocking mixture. The membrane was washed with
TBS-T and probed with ECL Plus (Amersham Corp.). Visualization and
quantification were performed using the Storm 860-blue
chemifluorescence scanner (Molecular Dynamics).
Statistical Methods.
Statistical analysis was performed using Statistica 5.1 software
(StatSoft, Tulsa, OK). Comparisons of means were carried out by
Student’s t test; differences with a value of
P < 0.05 were considered statistically significant.
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RESULTS |
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, the constitutive
expression of COX-2 is illustrated by a band at 4.2 kb, which is
consistent with the size of COX-2 mRNA (6)
. Western blot
analysis of cell lysates using an antihuman COX-2 polyclonal antibody
revealed a specific COX-2 protein expression in the form of a 66-kDa
band (Fig. 1B)
. It has been reported previously that four
potential N-glycosylation sites are present in COX-2, which
are variably occupied, depending on cell type (35)
. Thus,
the difference in the molecular weight of the maximum glycosylated form
of COX-2 (Mr 72,000) and
Mr 66,000 COX-2 detected in U251 cells
is consistent with differences in the used glycosylation sites, as
reported by others (33
, 35) . Together, the Northern and
Western blot analyses indicate that there is constitutive COX-2
expression in the U251 cell line. Exposure of U251 cells in
vitro to SC-236 had no effect on COX-2 protein levels as detected
by Western analysis (data not shown).
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. Although the SF was
reduced to 0.1 after 1 day of drug incubation, 2 days of SC-236
treatment resulted in significantly less cell killing. This was an
unexpected result; typically, an increase in the length of drug
exposure leads to an increase in the amount of cell killing. However,
it was noted that compared with 1 day of incubation, after 2 days of
SC-236 exposure, a significant number of cells had detached from the
monolayer and were floating in the medium. The colony-forming
efficiency assay used in these studies evaluates the survival of only
those cells attached to the flask. Therefore, to determine whether the
observed differences in the SF at 1 and 2 days of SC-236 exposure can
be accounted for by cell detachment, cells floating in the media were
quantified at each time point. As shown in Fig. 2B
, only a
small increase in the amount of floating cells was detected after 1 day
of SC-236 exposure. However, after 2 days of drug incubation, a
significant increase occurred in the proportion of floating cells,
which corresponded to a decrease in the proportion of attached cells.
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, only 1.2%
of the attached cells were apoptotic compared with 82.6% of the
floating cells. Thus, the difference in colony-forming efficiency
obtained at 1 and 2 days of SC-236 treatment is explained by the
characteristics of the cell-survival assay used and the mode of cell
death induced by SC-236, i.e., SC-236 kills U251 cells
through the induction of apoptosis, which results in cell detachment
from the monolayer. This process takes >24 h. After only 1 day of drug
incubation, all of the cells, including those destined to die via
apoptosis, remain attached to the flask in monolayer and are analyzed
by the colony-forming efficiency assay, which results in a low SF.
However, after 2 days, the floating cells, i.e., cells that
died because of apoptosis, are eliminated from the assay during the
trypsinization process, and only the nonapoptotic attached cells are
analyzed.
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-rays. The cells were then assayed for colony-forming
efficiency; the survival curves generated were corrected for cell
killing induced by the drug alone. As shown in Fig. 4
, SC-236 treatment for 1 day had no
significant effect on the radiosensitivity of U251 cells compared with
the untreated control cells. Treatment of U251 cells with SC-236 for 2
days, however, resulted in a significant increase in the level of
radiationinduced cell death. The dose enhancement factor at a SF
of 0.1 was 1.4, and the SF at 2 Gy was reduced from 0.61 to 0.31. The
failure to observe radiosensitization after 1 day of SC-236 exposure
may involve the significant level of cell death induced by the drug
alone at this time point. As shown in Fig. 2A
, SC-236 alone
reduces survival by 90%; it is unlikely that radiosensitization could
be detected in the remaining 10% of the population. However, at 2
days, the dead (apoptotic) cells were eliminated, and
radiosensitization was clearly detectable in the remaining attached
cells.
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, at 2 days after
drug treatment, only minor changes in U251 cell cycle phase
distribution were observed. The percentage of cells in the
G1, S, and G2-M cell cycle
phases for control and SC-236-treated cells were 75, 11, 14, and 72,
20, 8, respectively. Thus, an accumulation of cells in the
radiosensitive G2-M phase of the cell cycle does
not seem to account for the radiosensitization. Another possible
mechanism for SC-236-mediated radiosensitization is the disruption of a
cell cycle delay typically induced by radiation. As shown in Table 1
, radiation alone induces a
G2-M block in U251 cells; SC-236 does not affect
this cell cycle delay. At 3 and 4 days after SC-236 alone, the U251
cell cycle phase distribution was essentially the same as in Fig. 5
for
2 days of treatment (data not shown). To determine whether the
SC-236-mediated radiosensitization of U251 cells involves an increase
in the propensity of these cells to undergo apoptosis, flow cytometric
analysis of TUNEL-stained cells was performed. For SC-236 treatment
alone, after the apoptosis that occurred after 2 days (Fig. 3)
, no
additional apoptosis was detected (data not shown). Furthermore, no
increase in the percentage of apoptotic cells after the combination of
SC-236 and irradiation was detected (Table 1)
. Thus, the data in Fig. 4
and Table 1
suggest that SC-236-mediated radiosensitization is the
result of an enhancement of radiation-induced clonogenic cell death.
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The effects of SC-236 on the in vivo radioresponse of this
human tumor cell line were evaluated using a protocol found previously
to enhance the radioresponse of a murine tumor grown in syngenic hosts
(25)
. Animals bearing 5-mm-diameter tumors were given
SC-236 in drinking water (0.045 mg/ml) for 10 consecutive days. A
single dose of 10 Gy was given when these tumors grew to 7 mm in
diameter, which occurred 4–6 days later for both control and
drug-treated groups. Figure 6A
shows that SC-236 treatment alone inhibited tumor growth significantly;
the time required for tumors to grow from 5 to 12 mm in diameter was
increased from 8.9 ± 0.9 to 13.6 ± 0.7 days
(P < 0.01). To assess whether SC-236 enhances tumor
radioresponse, tumor-bearing mice were treated with SC-236 alone,
radiation alone, or the combination of the two, and tumor growth was
measured. As shown in Fig. 6B
, SC-236 greatly increased
radiation-induced growth delay. The absolute growth delays (the time in
days for tumors to grow from 7 to 12 mm in treated mice minus the time
in days for tumors to reach the same size in untreated mice) were 4.3
for SC-236 treatment only, 9.9 for radiation only, and 25.4 for the
combination. Thus, the growth delay after the combined treatment was
more than the sum of growth delays caused by radiation alone or SC-236
alone. The dose enhancement factor, obtained by dividing normalized
tumor growth delay in mice treated with SC-236 plus radiation with the
absolute growth delay in mice treated with radiation alone, was 2.13.
Normalized tumor growth delay is defined as the time in days for tumors
to grow from 7 to 12 mm in mice treated with the combination of SC-236
and radiation minus the time in days for tumors to grow from 7 to 12 mm
in mice treated with SC-236 alone. Thus, SC-236 alone slows tumor
growth and enhances the effect of ionizing radiation, with results
similar to the results obtained in vitro. No observable
toxicity was detected in any of the mice, which is consistent with the
preferential enhancement of tumor radioresponse compared with that of
normal tissue, as recently reported by Kishi et al.
(26)
.
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DISCUSSION |
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The data presented here show that the glioma cell line U251 expresses COX-2 at a level similar to that in the human colon cancer cell line HT29. Furthermore, exposure of U251 cells to SC-236 results in a significant reduction in cell survival, which can be attributed to the induction of apoptosis. This is similar to HT29 cells in which apoptosis was detected after exposure to the COX-2 inhibitor NS-398 (34) . However, in addition to reducing cell survival by approximately 90%, SC-236 enhanced the radiosensitivity of the remaining surviving cells. The antitumor and radiosensitizing effects of SC-236 were also detected in U251 cells grown as xenografts in nude mice. To our knowledge, this is the first demonstration of a selective COX-2 inhibitor affecting the intrinsic radiosensitivity of tumor cells. We recently reported (25) that SC-236 delivered in drinking water enhanced the in vivo radioresponse of a murine sarcoma designated NFSA, as determined by tumor growth delay and the dose yielding 50% tumor cure. In that study, the COX-2 inhibitor was shown to reduce NFSA neovascularization, which correlated with the radiosensitizing effect. The involvement of antiangiogenesis is a possibility, based on the increasing evidence demonstrating that the therapeutic effect of the combination of radiation and antiangiogenic compounds, such as angiostatin or TNP-470, is greater than additive (44 , 45) . Whether SC-236 enhanced the intrinsic radiosensitivity of the murine NFSA cells or whether SC-236 inhibited neovascularization of U251 cells in vivo remains to be determined. However, these studies illustrate two processes by which COX-2 inhibition can enhance the in vivo response of tumors to radiation.
The cellular and biochemical processes responsible for the
SC-236-mediated radiosensitization remain to be determined. Furuta
et al. (21)
showed that indomethacin, a
nonspecific NSAID, caused accumulation of cells in the
G2-M phase of the cell cycle, which is generally
considered to be the most sensitive to ionizing radiation. As
illustrated by DNA histograms (Fig. 5)
, no increase in the percentage
of U251 in G2-M was observed 2 days after drug
treatment, which corresponds to the time of radiosensitization. Another
possible mechanism would be a disruption in cell cycle delay typically
induced by radiation. As shown in Table 1
, radiation alone induces a
G2-M block in U251 cells, but SC-236 does not
affect this cell cycle delay. Although induction of
G2-M arrest after treatment with NSAIDs has been
reported for colon cancer cell lines (46)
, the data
presented here suggest that cell cycle modification is not involved in
the SC-236-induced radiosensitization of U251 cells.
An additional process that may account for the effects of SC-236 is the shifting of the mode of radiation-induced cell death from clonogenic to apoptotic, which has received considerable attention as a means of radiosensitization. Indeed, Elder et al. (34) recently reported an increase in the number of detached cells from cultured human colon carcinoma cell lines in response to NS-398, a COX-2 selective inhibitor, which was attributable almost entirely to the induction of apoptosis. To determine whether the SC-236-mediated radiosensitization of U251 cells involves an induction of apoptosis, TUNEL staining was performed after combined treatment. In contrast with the apoptosis that occurred after 2 days of treatment with SC-236 alone, no increase in the percentage of apoptotic cells after the combination of SC-236 with irradiation was detected, which suggests that SC-236-mediated radiosensitization is the result of an enhancement of radiation-induced clonogenic cell death.
In summary, our findings demonstrate that the selective COX-2 inhibitor SC-236 is cytotoxic to U251 glioma cells in vitro because of induction of apoptosis and that it enhances the radiosensitivity of the surviving cells. Furthermore, these in vitro results correlated with the effects of SC-236 alone and in combination with radiation on U251 xenografts. Thus, the selective inhibition of COX-2 in combination with radiation may have potential as a treatment for human brain tumors.
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at University of Texas M. D. Anderson Cancer, Department of
Experimental Radiation Oncology, 1515 Holcombe Boulevard, Box 66,
Houston, Texas 77030. Phone: (713) 792-3424; Fax: (713) 794-5369;
E-mail: ptofilon{at}notes.mdacc.tmc.edu 
2 The abbreviations used are: PG, prostaglandin;
COX, cyclooxygenase; FCM, flow cytometry; TdT, terminal
deoxynucleotidyl transferase; TUNEL, TdT-mediated nick end labeling;
SF, surviving fraction; NSAID, nonsteroidal anti-inflammatory drug;
CNS, central nervous system.
Received 12/16/99; revised 2/17/00; accepted 3/ 7/00.
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, treated mice. B, effect
of the combination of SC-236 treatment and local irradiation on tumor
growth: vehicle control (•), SC-236 (
),
SC-236 plus 10-Gy single-dose irradiation (
). Values shown, the
means ± SE of 7–10 mice.