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Experimental Therapeutics |
Departments of Medicine [C. S. W., H. S., R. H., J. S., R. N. D.], and Cell Biology, [C. S. W., R. N. D.], The Vanderbilt Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2279; Veterans Administration Medical Center [R. N. D.], Nashville, Tennessee 37232-2279; and Department of Medicine, University of Liverpool, Liverpool, United Kingdom [A. J. M. W.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Numerous epidemiological studies indicate that chronic use of NSAIDs3 lowers the mortality rate from colorectal cancer (1 , 2) . NSAIDs are effective at inducing regression of existing polyps in familial adenomatous polyposis patients (3) and in reducing the tumor burden in three animal models of colorectal cancer: the multiple intestinal neoplasia mouse (4 , 5) , the azoxymethane-treated rat model (6) , and the nude mouse xenograft model (7, 8, 9) .
NSAIDs inhibit the activity of the cyclooxygenases, which are key enzymes in the conversion of arachidonate to PGH2, the immediate substrate for a number of specific prostaglandin synthases. Unfortunately, prolonged use of NSAIDs can result in gastrointestinal ulceration and bleeding. It is widely believed that this ulcerogenic activity of NSAIDs is attributable to the chronic inhibition of prostaglandin production in the gastric mucosa. Accordingly, researchers have tried to identify NSAID derivatives that retain anti-neoplastic activity but do not affect prostaglandin production in gastric mucosa.
There are two isoforms of cyclooxygenase, COX-1 and COX-2, which differ in their expression pattern and function within the organism. COX-1 is constitutively expressed in many tissues and is thought to be responsible for maintaining gastric mucosal integrity. COX-2 is induced by a variety of stimuli and plays an important role in wound healing, ovulation, fertilization, and in mediating inflammation (for review, see Ref. 10 ). COX-2 expression levels are increased in colorectal cancer tissues (11, 12, 13, 14) . Overexpression of COX-2 has been shown to mediate cell cycle progression and to contribute to such diverse processes such as apoptosis, angiogenesis (15) , and tissue invasion (16) . On the basis of these effects, we have investigated the role of specific COX-2 inhibitors in the treatment of advanced colorectal cancer.
We have studied previously the effects of a selective COX-2 inhibitor, SC-58125, on the growth and viability of colorectal carcinoma cells grown in vitro and in vivo (7) . The precise mechanism for growth inhibition of tumors is under evaluation, but does not seem to involve the induction of apoptosis in vivo (17) . It has been reported that nonselective COX inhibitors induce a G2-M cell cycle arrest resulting in a corresponding reduction of p34cdc2 levels and activity (18) . We have observed a similar effect after SC-58125 treatment of colorectal carcinoma cells.4 These results suggest that SC-58125 may have therapeutic potential for treatment of colorectal cancer. However, SC-58125 will not be developed for clinical use in humans. Furthermore, although SC-58125 reduces tumor growth, it does not cause tumor regression (7 , 9) . Therefore, we evaluated other COX-2 inhibitors for their effect on the growth of colorectal carcinoma cells in vitro and in vivo.
Here we report that celecoxib (Celebrex), at concentrations >10
µM, potently induces apoptosis and inhibits cell cycle
progression in colorectal carcinoma cells grown in culture by
mechanisms independent of COX-2 inhibition. Lower concentrations of the
drug have no discernible effect on cells grown in vitro. We
also found that when celecoxib was administered to mice by inclusion in
the diet (1250 mg/kg of chow), serum concentrations of 
2.3
µM were achieved. Nevertheless, in contrast to
the results from cell culture experiments, celecoxib significantly
reduced the growth rate of colorectal carcinoma cells grown as
xenografts, without toxicity to the normal intestine. These data
highlight the point that the biological effects of celecoxib against
cells grown in culture do not predict its effects in vivo.
However, these findings do support additional investigation for the use
of celecoxib as a therapeutic agent against colorectal cancer.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Culture.
HCA-7 cells were a generous gift from Susan Kirkland. LLC and HCT-15
cells and HCT-116 cells were purchased from the American Type Tissue
Collection (Manassas, VA).
MEF Derivation.
Primary MEFs were derived by passing day 13.5 C57BL/6J mouse embryos
through an 18-gauge needle. The cells were expanded over several days
in DMEM supplemented with 10% FBS, 1% P/S/1%
L-glutamine. The cox-2 genotype of the MEF cell
lines was verified as described previously (19)
.
Cell Counts.
LLC cells were seeded into six-well plates at 2.5 x 104
cells/well. Cells were treated in triplicate
with DMSO or 25, 50, or 100 µM celecoxib for 12 h
and then harvested and counted using a Coulter counter model Z1
(Coulter, Fullerton, CA).
In Vitro Viability Assay.
The MTT assay was used to determine cell
viability/proliferation. This assay measures mitochondrial activity.
MTT is a yellow-colored tetrazolium salt that is taken up and cleaved
only by metabolically active cells, reducing it to a colored,
water-insoluble formazan salt. The solubilized formazan product can be
quantified via absorbance at 570 nm measured using a 96-well-format
spectrophotometer, and the absorbance correlates directly with cell
number. Cells were plated at 1.5 x 104
cells/well in a 100-µl volume in 96-well
plates and grown for 24 h in DMEM supplemented with 10% FBS. The
indicated amount of test drug or DMSO in 1% FBS containing OptiMEM
media was then added to the wells. At the indicated times, 10 µl of
MTT (5 mg/ml) was added, and the cells were incubated at 37°C for
4 h. The tetrazolium crystals were solubilized by the addition of
10% SDS in 0.01 N HCl. After overnight
incubation at 37°C, the absorbance was measured at 570 nm using a
96-well spectrophotometric plate reader (Packard Instruments, Meriden,
CT). Results are expressed as the mean ± SD of six
wells.
Prostaglandin Measurement.
Subconfluent cell cultures were treated with either celecoxib or
SC-58125 for the indicated time. Thirty min before harvesting media,
arachidonate was added to the media to a final concentration of 10
µM.
PGE2 was quantified
as described previously (20)
.
Apoptosis Determination.
The APO-Direct kit (PharMingen, San Diego, CA) was used for
quantitative evaluation of apoptosis in response to celecoxib
treatment. This assay relies on the characteristic fragmentation of DNA
during the apoptotic process. Terminal nucleotide transferase enzyme is
used to end-label the free 3'-OH of fragmented DNA using
fluorescein-conjugated dUTP is used as the nucleotide for the exchange
reaction. Flow cytometric detection of fluorescein-labeled
fragmented DNA was conducted to quantitatively evaluate apoptosis in
response to celecoxib treatment. Cells were seeded in 100-mm plates,
and when 80% confluent cells were treated with DMSO, or 12.5,
25, or 50 µM celecoxib in 1% FBS-supplemented OptiMEM
media. Negative control cells were not treated; vehicle-treated cells
had an amount of DMSO equivalent to the celecoxib-treated cells
added. Cells were harvested after 12 h of treatment, washed
in PBS twice then fixed in 1% paraformaldehyde for 15 min and
permeabilized by the addition of ice-cold 70% ethanol. The labeling
reaction was performed according to the manufacturer’s
recommendations, with the exception that 2 x 106 cells/condition were used. After labeling,
cells were washed three times in PBS, then resuspended in 1 ml of
propidium iodide staining solution (5 µg/ml propidium iodide, 40
µg/ml RNASE A, in 1 x PBS). Cells were then filtered
through 50-µm mesh immediately before analysis on a Becton Dickinson
FACScan flow cytometer. Gating on FL2-width was used to exclude
aggregates, and 104
gated events were collected
and analyzed.
Xenograft Model of Tumor Biology.
HCA-7 cells were grown on plastic culture dishes according to standard
cell culture techniques (7)
. The cells were trypsinized
and resuspended in sterile PBS, then pelleted by brief centrifugation
at 1500 rpm. The supernatant was aspirated, and cells were resuspended
in PBS and counted using a hemocytometer. A final concentration of
5 x 107 cells/ml was made, and
100 µl of cell suspension was injected s.c. using a tuberculin
syringe and a 27-gauge needle. Celecoxib was administered in the diet
(1250 mg/kg of chow) and the animals were fed ad libitum.
The size of the tumor was determined by direct measurement of tumor
dimensions as described previously (7)
.
Scoring Apoptosis and Mitosis in Normal Intestinal Epithelium.
In brief, mice were fed celecoxib (1250 mg/kg of chow) and the small
and large intestines were removed separately and prepared by methods
described in detail elsewhere (21
, 22)
. Apoptotic bodies
were identified by their characteristic morphological appearance in
sections stained with H&E. To score the sections, each cell along the
long axis of the crypt was numbered sequentially from the base of the
crypt; the cell at the crypt base was designated as number 1. Each cell
position was scored as containing either a normal, mitotic, or
apoptotic cell. For each cell position, apoptotic and mitotic
percentages were calculated. We have already shown this methodology to
be more accurate when examining tissues than when identifying apoptotic
bodies by TUNEL staining (23)
.
Gut Morphometry.
Villus height and crypt depth was measured on an Axiohome microscope on
20 crypts and 20 villi from at least six animals/experimental group.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, left panel). As with SC-58125, we found that
celecoxib inhibited the growth of LLC cells but was much more potent.
After only 12 h of treatment, the IC50 for
celecoxib inhibition of cell number was 40 µM
(Fig. 1A
, right panel). The cytotoxicity of
celecoxib against LLC cells was also quantified using the MTT assay.
When celecoxib concentrations of <10 µM were
used, no effect on cell viability or growth was
observed.5
However, treatment for 12 h with >20 µM
celecoxib resulted in a dramatic decrease in cell viability (Fig. 1B)
. We next determined whether celecoxib also had potent
cytotoxicity against two human colorectal carcinoma cell lines (HCT-15
and HCA-7). Celecoxib had similar cytotoxic effects against these cells
with significant loss of viability at concentrations of >20
µM (Fig. 1B)
. Once again, treatment
of these cells with celecoxib for 3 days at concentrations of <10
µM had no effect on cell viability.
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. We found that LLC and HCA-7 cells undergoing apoptosis contained 4
N DNA content, suggesting that arrest at the
G2-M stage of the cell cycle was occurring. In
contrast, apoptotic HCT-15 cells contained a subdiploid DNA content
after celecoxib treatment, suggesting that apoptosis was occurring when
the cells contained 2 N DNA. The induction of apoptosis was
confirmed by the detection of oligonucleosomal cleavage of DNA in LLC
and HCA-7 cells after treatment with 50 µM celecoxib for
6 h.5
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. The lack of correlation between COX-2 inhibitory activity
and cytotoxicity suggests that the effect of celecoxib in
vitro is independent of its ability to inhibit COX-2. One possible
explanation for the different effects of celecoxib and SC-58125 on
carcinoma cells might be attributable to variation in inhibition
profiles or half-lives of these compounds. We next compared inhibition
of PGE2 production by celecoxib and SC-58125.
Celecoxib inhibits PGE2 production in LLC cells
with an IC50 of 18 nM. Both
compounds had similar cyclooxygenase inhibition profiles, decreasing
PGE2 levels by 85–95% for at least 12 h
after treatment (Fig. 3
B.2, right panel).
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. Furthermore, the concentration dependence of
cytotoxicity for the cell lines of all three MEFs and LLC cells
were similar (Fig. 3C)
. As with the colon carcinoma cells
tested (Fig. 1B)
, no cell death was observed at celecoxib
concentrations of <10 µM. These results
strongly indicate that the cytotoxicity of celecoxib in
vitro is independent of inhibition of COX-2 and brings up the
question of whether this drug is cytotoxic in vivo.
Celecoxib Does Not Cause Apoptosis or Inhibit Cell Division in
Normal Gut Epithelium.
The COX-2 independent toxicity of celecoxib to MEFs raises the
possibility that celecoxib might cause significant apoptosis and/or
cell cycle arrest in normal gut epithelium. Therefore, we determined
apoptotic and mitotic rates in the small and large intestinal
epithelium of nude mice fed celecoxib (1250 mg/kg chow) for 45 days. As
described previously, spontaneous rates of apoptosis in the mouse
intestine were found to be low (23)
. Treatment with
celecoxib for 45 days did not cause any significant change in apoptotic
or mitotic rates in either the small or large intestine (Fig. 4A)
. Evaluation of intestinal epithelium 4 h after
administration of a single dose of celecoxib did not reveal increased
rates of apoptosis.5
Furthermore, no significant
differences in gut morphology could be discerned. In the small
intestine, villus height was 303 ± 95 versus
289 ± 86 µm in control and celecoxib-treated animals,
and crypt depth was 100.4 ± 17 µm in control animals
and 100 ± 38 µm treated mice. Similarly, the colon
crypt length was unaffected by treatment with celecoxib 150 ± 25 µm in control colon versus 167 ± 31 µm in treated colon.
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). Thus the peak serum concentration of celecoxib achieved
in mice using this dosing regime was 10-fold less than that which led
to cytotoxicity in vitro.
In Vivo Tumor Growth Is Attenuated by Celecoxib
Treatment.
We have reported previously that celecoxib attenuates the growth of LLC
tumors in vivo (17)
. Given the recent interest
in the use of COX-2 inhibitors for chemoprevention of colorectal
cancer, we wished to confirm and extend these observations in a
colorectal carcinoma cell line. HCA-7 cells were implanted s.c. into
athymic mice. Celecoxib was mixed with mouse chow at a concentration of
1250 mg/kg. (The xenograft and normal intestinal studies reported above
were performed in the same mice). Whereas data from our in
vitro studies may predict that such a low dose of celecoxib (2.3
µM) would be ineffective at inhibiting tumor
growth, we found that the growth of HCA-7 xenograft growth was
significantly reduced when compared with animals on the control diet
(Fig. 5)
. Delaying treatment for 10, 20, or 30 days postimplantation, by which
point the tumors were well established, still resulted in inhibition of
tumor growth, indicating that the compound was not affecting tumor
implantation (Fig. 5)
. These data demonstrate that celecoxib prevents
the growth of colorectal carcinoma cells in vivo at
concentrations that do not cause apoptosis in cells grown in
vitro.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At concentrations >20 µM, celecoxib induces cell death
as measured by cell counts of LLC cells and the assay of LLC, HCA-7,
and HCT-15 cells (Fig. 1)
. Analysis of TUNEL staining by flow
cytometery (Fig. 2)
and the demonstration of oligonucleosomal DNA
cleavage confirms that the loss of viability is attributable to the
induction of apoptosis. In addition, a G2-M block
is also induced in LLC and HCA-7 cells by treatment with 50
µM celecoxib. Interestingly, in HCT-15 cells we observed
a subdiploid accumulation of fragmented DNA suggesting that apoptosis
was occurring during the G1 to early S transition
of the cell cycle. These results show that celecoxib, at concentrations
>20 µM, strongly induces apoptosis in cells grown
in vitro.
Three lines of evidence indicated that induction of apoptosis in
vitro by high-dose celecoxib occurs by mechanisms independent of
COX-2 inhibition: (a) the cytotoxicity of a variety of
NSAIDs did not correlate with their ability to inhibit COX-2 (Fig. 3A)
; (b) although SC-58125 and celecoxib can both
inhibit PGE2 production by >90% at a
concentration of 10 µM, SC-58125 at 50
µM has no effect on cell viability, whereas
celecoxib reduces viability by 70% when given at that concentration;
and (c) MEFs derived from wild-type, cox-2
heterozygous or cox-2 null C57/BL6 mice have similar
sensitivities to the cytotoxic effects of celecoxib. These results
provide compelling evidence that the cytotoxicity of these agents
in vitro is independent of COX-2 inhibition, and indicates
that high-dose celecoxib is cytotoxic not only to carcinoma cells
in vitro, but also to nontransformed mammalian cells grown
in culture.
A crucial observation from these studies is that treatment with 10
µM or less of celecoxib for 3 days has no detectable
effect on cell death in vitro. Despite this lack of effect
in cultured cells, we found that celecoxib strongly attenuated the
growth of xenografted HCA-7 tumors in vivo, although the
plasma concentration of celecoxib was 2.3
µM. This discrepancy highlights the fact that
tumor growth in vivo is determined by the interaction
between factors intrinsic to tumor cells, the extracellular matrix,
stromal cells, and other host factors. These factors are not always
present in vitro when cells are grown on plastic culture
dishes. Cell culture models are often used to evaluate the therapeutic
potential of NSAIDs against cancer, but great caution needs to be taken
when extrapolating in-vitro results to the whole organism,
particularly with respect to the relative dose of agent used.
These studies do not address the issue of the mechanism by which celecoxib attenuates tumor growth in vivo or evaluate its COX-2 dependency. In vivo, interference with the implantation of carcinoma cells does not seem to play a significant role because growth is still affected even when treatment is started 30 days after inoculation of the host. It has not been well established that COX-2 expression in the carcinoma cells in vivo contributes to tumor growth. Previous studies using tumor models lacked the ability to distinguish between tumor-derived COX-2 and extrinsic COX-2. We recently have reported that stromally derived COX-2 is important for tumor growth (17) . It is possible that whereas low doses of celecoxib do not affect tumor cells in vitro, stromal or host-derived processes dependent on COX-2 may be sensitive to low-dose NSAID treatment. Angiogenesis, a necessary component of neoplastic growth, is also promoted by COX-2 activity, and its inhibition could play a crucial role in the antineoplastic action of celecoxib (15 , 17 , 24 , 25) .
In striking contrast to the antitumor effects of celecoxib, no toxic effects were observed in the normal gut by assessing induction of apoptosis, inhibition of cell division, or reduction of crypt and villus dimensions. The explanation for the differential effect of celecoxib on normal and transformed intestinal epithelial tissue is not known, but it is interesting to note that COX-2 expression and activity is very low to undetectable in normal gut mucosa. Furthermore, gut epithelium is not as dependent on new-vessel growth as tumor xenografts.
In summary, celecoxib can significantly attenuate the growth of colorectal carcinoma xenografts without adverse effects on the normal gut. Although celecoxib causes apoptosis of colorectal cancer cells grown in vitro via a COX-2-independent mechanism, this only occurs at concentrations >10-fold higher than what can be achieved in vivo. Great caution should be taken in interpreting the clinical significance of cell culture data, particularly with respect to drug levels that could be safely achieved in humans. Overall, celecoxib seems to have significant therapeutic potential against colorectal cancer, and additional clinical evaluation is warranted.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported in part by USPHS Grants
RO1DK-47297 (to R. N. D.), P30CA-68485 (to R. N. D.) and
PO1CA-77839 (to R. N. D.). A. J. M. W. is supported by Grant 97/21
from the Association of International Cancer Research. R. N. D. is a
recipient of a Veterans Affairs Research Merit Grant and the
Mina C. Wallace Professor of Medicine. 
2 To whom requests for reprints should be
addressed, at Department of Medicine/GI; MCN C-2104, Vanderbilt
University Medical Center, 1161 21st Avenue South, Nashville, TN
37232-2279. Phone: (615) 343-4747; Fax: (615) 343-6229; E-mail: raymond.dubois{at}mcmail.vanderbilt.edu
3 The abbreviations used are: NSAID, nonsteroidal
anti-inflammatory drug; LLC, Lewis lung carcinoma; MEF, mouse embryo
fibroblast; TUNEL, terminal deoxynucleotidyl transferase-mediated nick
end labeling; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide; FBS, fetal bovine serum; PGE2, prostaglandin
E2.
Received 5/31/00. Accepted 9/ 1/00.
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M. Murakami, S. Masuda, K. Ueda-Semmyo, E. Yoda, H. Kuwata, Y. Takanezawa, J. Aoki, H. Arai, H. Sumimoto, Y. Ishikawa, et al. Group VIB Ca2+-independent Phospholipase A2{gamma} Promotes Cellular Membrane Hydrolysis and Prostaglandin Production in a Manner Distinct from Other Intracellular Phospholipases A2 J. Biol. Chem., April 8, 2005; 280(14): 14028 - 14041. [Abstract] [Full Text] [PDF]
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 S. S.A. Qadri, J.-H. Wang, J. C. Coffey, M. Alam, A. O'Donnell, T. Aherne, and H. P. Redmond Surgically Induced Accelerated Local and Distant Tumor Growth is Significantly Attenuated by Selective COX-2 Inhibition Ann. Thorac. Surg., March 1, 2005; 79(3): 990 - 995. [Abstract] [Full Text] [PDF]
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M. I. Patel, K. Subbaramaiah, B. Du, M. Chang, P. Yang, R. A. Newman, C. Cordon-Cardo, H. T. Thaler, and A. J. Dannenberg Celecoxib Inhibits Prostate Cancer Growth: Evidence of a Cyclooxygenase-2-Independent Mechanism Clin. Cancer Res., March 1, 2005; 11(5): 1999 - 2007. [Abstract] [Full Text] [PDF]
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D. Cervi, G. Klement, D. Stempak, S. Baruchel, A. Koki, and Y. Ben-David Targeting Cyclooxygenase-2 Reduces Overt Toxicity toward Low-Dose Vinblastine and Extends Survival of Juvenile Mice with Friend Disease Clin. Cancer Res., January 15, 2005; 11(2): 712 - 719. [Abstract] [Full Text] [PDF]
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 X. Liu, P. Yue, Z. Zhou, F. R. Khuri, and S.-Y. Sun Death Receptor Regulation and Celecoxib-Induced Apoptosis in Human Lung Cancer Cells J Natl Cancer Inst, December 1, 2004; 96(23): 1769 - 1780. [Abstract] [Full Text] [PDF]
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D. S. Dandekar and B. L. Lokeshwar Inhibition of Cyclooxygenase (COX)-2 Expression by Tet-Inducible COX-2 Antisense cDNA in Hormone-Refractory Prostate Cancer Significantly Slows Tumor Growth and Improves Efficacy of Chemotherapeutic Drugs Clin. Cancer Res., December 1, 2004; 10(23): 8037 - 8047. [Abstract] [Full Text] [PDF]
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B. A. Narayanan, N. K. Narayanan, B. Pittman, and B. S. Reddy Regression of Mouse Prostatic Intraepithelial Neoplasia by Nonsteroidal Anti-inflammatory Drugs in the Transgenic Adenocarcinoma Mouse Prostate Model Clin. Cancer Res., November 15, 2004; 10(22): 7727 - 7737. [Abstract] [Full Text] [PDF]
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A J M Watson Apoptosis and colorectal cancer Gut, November 1, 2004; 53(11): 1701 - 1709. [Full Text] [PDF]
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 G. D. Basu, L. B. Pathangey, T. L. Tinder, M. LaGioia, S. J. Gendler, and P. Mukherjee Cyclooxygenase-2 Inhibitor Induces Apoptosis in Breast Cancer Cells in an In vivo Model of Spontaneous Metastatic Breast Cancer Mol. Cancer Res., November 1, 2004; 2(11): 632 - 642. [Abstract] [Full Text] [PDF]
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H. Okano, H. Shinohara, A. Miyamoto, K. Takaori, and N. Tanigawa Concomitant Overexpression of Cyclooxygenase-2 in HER-2-Positive on Smad4-Reduced Human Gastric Carcinomas Is Associated with a Poor Patient Outcome Clin. Cancer Res., October 15, 2004; 10(20): 6938 - 6945. [Abstract] [Full Text] [PDF]
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 S. Shishodia, D. Koul, and B. B. Aggarwal Cyclooxygenase (COX)-2 Inhibitor Celecoxib Abrogates TNF-Induced NF-{kappa}B Activation through Inhibition of Activation of I{kappa}B{alpha} Kinase and Akt in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of COX-2 Synthesis J. Immunol., August 1, 2004; 173(3): 2011 - 2022. [Abstract] [Full Text] [PDF]
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S. Shishodia and B. B. Aggarwal Cyclooxygenase (COX)-2 Inhibitor Celecoxib Abrogates Activation of Cigarette Smoke-Induced Nuclear Factor (NF)-{kappa}B by Suppressing Activation of I-{kappa}B {alpha} Kinase in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of Cyclin D1, COX-2, and Matrix Metalloproteinase-9 Cancer Res., July 15, 2004; 64(14): 5004 - 5012. [Abstract] [Full Text] [PDF]
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C. T. Dang, A. J. Dannenberg, K. Subbaramaiah, M. N. Dickler, M. M. Moasser, A. D. Seidman, G. M. D'Andrea, M. Theodoulou, K. S. Panageas, L. Norton, et al. Phase II Study of Celecoxib and Trastuzumab in Metastatic Breast Cancer Patients Who Have Progressed after Prior Trastuzumab-Based Treatments Clin. Cancer Res., June 15, 2004; 10(12): 4062 - 4067. [Abstract] [Full Text] [PDF]
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D. Wei, L. Wang, Y. He, H. Q. Xiong, J. L. Abbruzzese, and K. Xie Celecoxib Inhibits Vascular Endothelial Growth Factor Expression in and Reduces Angiogenesis and Metastasis of Human Pancreatic Cancer via Suppression of Sp1 Transcription Factor Activity Cancer Res., March 15, 2004; 64(6): 2030 - 2038. [Abstract] [Full Text] [PDF]
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M. Pold, L. X. Zhu, S. Sharma, M. D. Burdick, Y. Lin, P. P. N. Lee, A. Pold, J. Luo, K. Krysan, M. Dohadwala, et al. Cyclooxygenase-2-Dependent Expression of Angiogenic CXC Chemokines ENA-78/CXC Ligand (CXCL) 5 and Interleukin-8/CXCL8 in Human Non-Small Cell Lung Cancer Cancer Res., March 1, 2004; 64(5): 1853 - 1860. [Abstract] [Full Text] [PDF]
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T. Wu, J. Leng, C. Han, and A. J. Demetris The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells Mol. Cancer Ther., March 1, 2004; 3(3): 299 - 307. [Abstract] [Full Text]
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C. Han, J. Leng, A. J. Demetris, and T. Wu Cyclooxygenase-2 Promotes Human Cholangiocarcinoma Growth: Evidence for Cyclooxygenase-2-Independent Mechanism in Celecoxib-Mediated Induction of p21waf1/cip1 and p27kip1 and Cell Cycle Arrest Cancer Res., February 15, 2004; 64(4): 1369 - 1376. [Abstract] [Full Text] [PDF]
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S. K. Kulp, Y.-T. Yang, C.-C. Hung, K.-F. Chen, J.-P. Lai, P.-H. Tseng, J. W. Fowble, P. J. Ward, and C.-S. Chen 3-Phosphoinositide-Dependent Protein Kinase-1/Akt Signaling Represents a Major Cyclooxygenase-2-Independent Target for Celecoxib in Prostate Cancer Cells Cancer Res., February 15, 2004; 64(4): 1444 - 1451. [Abstract] [Full Text] [PDF]
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M. S. Shaik, A. Chatterjee, and M. Singh Effect of a Selective Cyclooxygenase-2 Inhibitor, Nimesulide, on the Growth of Lung Tumors and Their Expression of Cyclooxygenase-2 and Peroxisome Proliferator- Activated Receptor-{gamma} Clin. Cancer Res., February 15, 2004; 10(4): 1521 - 1529. [Abstract] [Full Text] [PDF]
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G. Ferrandina, F. O. Ranelletti, F. Legge, L. Lauriola, V. Salutari, M. Gessi, A. C. Testa, U. Werner, P. Navarra, G. Tringali, et al. Celecoxib Modulates the Expression of Cyclooxygenase-2, Ki67, Apoptosis-Related Marker, and Microvessel Density in Human Cervical Cancer: A Pilot Study Clin. Cancer Res., October 1, 2003; 9(12): 4324 - 4331. [Abstract] [Full Text] [PDF]
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B. A. Narayanan, M. S. Condon, M. C. Bosland, N. K. Narayanan, and B. S. Reddy Suppression of N-Methyl-N-nitrosourea/Testosterone-induced Rat Prostate Cancer Growth by Celecoxib: Effects on Cyclooxygenase-2, Cell Cycle Regulation, and Apoptosis Mechanism(s) Clin. Cancer Res., August 1, 2003; 9(9): 3503 - 3513. [Abstract] [Full Text] [PDF]
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R. A. Gupta, L. V. Tejada, B. J. Tong, S. K. Das, J. D. Morrow, S. K. Dey, and R. N. DuBois Cyclooxygenase-1 is Overexpressed and Promotes Angiogenic Growth Factor Production in Ovarian Cancer Cancer Res., March 1, 2003; 63(5): 906 - 911. [Abstract] [Full Text] [PDF]
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G.-H. Lai, Z. Zhang, and A. E. Sirica Celecoxib Acts in a Cyclooxygenase-2-independent Manner and in Synergy with Emodin to Suppress Rat Cholangiocarcinoma Growth in Vitro through a Mechanism Involving Enhanced Akt Inactivation and Increased Activation of Caspases-9 and -3 Mol. Cancer Ther., March 1, 2003; 2(3): 265 - 271. [Abstract] [Full Text] [PDF]
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G. Liu, W.-Y. Ma, A. M. Bode, Y. Zhang, and Z. Dong NS-398 and Piroxicam Suppress UVB-induced Activator Protein 1 Activity by Mechanisms Independent of Cyclooxygenase-2 J. Biol. Chem., January 17, 2003; 278(4): 2124 - 2130. [Abstract] [Full Text] [PDF]
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R. J. Levitt and M. Pollak Insulin-like Growth Factor-I Antagonizes the Antiproliferative Effects of Cyclooxygenase-2 Inhibitors on BxPC-3 Pancreatic Cancer Cells Cancer Res., December 15, 2002; 62(24): 7372 - 7376. [Abstract] [Full Text] [PDF]
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R. N. DuBois New Agents for Cancer Prevention J Natl Cancer Inst, December 4, 2002; 94(23): 1732 - 1733. [Full Text] [PDF]
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S. S. A. Qadri, J. H. Wang, K. C. Redmond, A. F. O'Donnell, T. Aherne, and H. P. Redmond The role of COX-2 inhibitors in lung cancer Ann. Thorac. Surg., November 1, 2002; 74(5): 1648 - 1652. [Abstract] [Full Text] [PDF]
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S. Arico, S. Pattingre, C. Bauvy, P. Gane, A. Barbat, P. Codogno, and E. Ogier-Denis Celecoxib Induces Apoptosis by Inhibiting 3-Phosphoinositide-dependent Protein Kinase-1 Activity in the Human Colon Cancer HT-29 Cell Line J. Biol. Chem., July 26, 2002; 277(31): 27613 - 27621. [Abstract] [Full Text] [PDF]
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E. T. Hawk, J. L. Viner, A. Dannenberg, and R. N. DuBois COX-2 in Cancer--A Player That's Defining the Rules J Natl Cancer Inst, April 17, 2002; 94(8): 545 - 546. [Full Text] [PDF]
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C. Waskewich, R. D. Blumenthal, H. Li, R. Stein, D. M. Goldenberg, and J. Burton Celecoxib Exhibits the Greatest Potency amongst Cyclooxygenase (COX) Inhibitors for Growth Inhibition of COX-2-negative Hematopoietic and Epithelial Cell Lines Cancer Res., April 1, 2002; 62(7): 2029 - 2033. [Abstract] [Full Text] [PDF]
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 J. M. Wallace Nutritional and Botanical Modulation of the Inflammatory Cascade--Eicosanoids, Cyclooxygenases, and Lipoxygenases-- As an Adjunct in Cancer Therapy Integr Cancer Ther, March 1, 2002; 1(1): 7 - 37. [Abstract] [PDF]
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M. J. Thun, S. J. Henley, and C. Patrono Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues J Natl Cancer Inst, February 20, 2002; 94(4): 252 - 266. [Abstract] [Full Text] [PDF]
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K. M. Leahy, R. L. Ornberg, Y. Wang, B. S. Zweifel, A. T. Koki, and J. L. Masferrer Cyclooxygenase-2 Inhibition by Celecoxib Reduces Proliferation and Induces Apoptosis in Angiogenic Endothelial Cells in Vivo Cancer Res., February 1, 2002; 62(3): 625 - 631. [Abstract] [Full Text] [PDF]
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O. J. Sansom, L. A. Stark, M. G. Dunlop, and A. R. Clarke Suppression of Intestinal and Mammary Neoplasia by Lifetime Administration of Aspirin in ApcMin/+ and ApcMin/+, Msh2-/- Mice Cancer Res., October 1, 2001; 61(19): 7060 - 7064. [Abstract] [Full Text] [PDF]
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R. D. Blumenthal, C. Waskewich, D. M. Goldenberg, W. Lew, C. Flefleh, and J. Burton Chronotherapy and Chronotoxicity of the Cyclooxygenase-2 Inhibitor, Celecoxib, in Athymic Mice Bearing Human Breast Cancer Xenografts Clin. Cancer Res., October 1, 2001; 7(10): 3178 - 3185. [Abstract] [Full Text] [PDF]
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R. N. DuBois Cyclooxygenease-2 and Hepatocellular Carcinoma: Is It a Target for Prevention? Clin. Cancer Res., May 1, 2001; 7(5): 1110 - 1110. [Full Text]
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