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Cancer Therapy: Preclinical |
1 Department of Medicine, Weill Medical College of Cornell University; Departments of 2 Urology, 3 Epidemiology and Biostatistics, and 4 Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; 5 Department of Surgery, University of Sydney, Sydney, Australia; and 6 Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Andrew J. Dannenberg, New York Presbyterian-Cornell, 525 East 68th Street, Room F-206, New York, NY 10021. Phone: 212-746-4403; Fax: 212-746-4885; E-mail: ajdannen{at}med.cornell.edu.
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ABSTRACT |
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Experimental Design: PC3 and LNCaP human prostate cancer cell lines were used to investigate the growth inhibitory effects of selective COX-2 inhibitors in vitro. To complement these studies, we evaluated the effect of celecoxib on the growth of PC3 xenografts.
Results: COX-1 but not COX-2 was detected in PC3 and LNCaP cells. Clinically achievable concentrations (2.5-5.0 µmol/L) of celecoxib inhibited the growth of both cell lines in vitro, whereas rofecoxib had no effect over the same concentration range. Celecoxib inhibited cell growth by inducing a G1 cell cycle block and reducing DNA synthesis. Treatment with celecoxib also led to dose-dependent inhibition of PC3 xenograft growth without causing a reduction in intratumor prostaglandin E2. Inhibition of tumor growth occurred at concentrations (2.37-5.70 µmol/L) of celecoxib in plasma that were comparable with the concentrations required to inhibit cell growth in vitro. The highest dose of celecoxib led to a 52% reduction in tumor volume and an 
50% decrease in both cell proliferation and microvessel density. Treatment with celecoxib caused a marked decrease in amounts of cyclin D1 both in vitro and in vivo.
Conclusions: Two clinically available selective COX-2 inhibitors possess different COX-2-independent anticancer properties. The anticancer activity of celecoxib may reflect COX-2-independent in addition to COX-2-dependent effects.
Key Words: Cyclooxygenase-2 • prostaglandin • angiogenesis
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Multiple lines of evidence suggest that COX-2 is a promising target for the prevention and treatment of cancer. COX-2 is commonly overexpressed in premalignant and malignant tissues (11–17). The most specific data supporting a cause-and-effect relationship between COX-2 and carcinogenesis come from genetic studies. Multiparous female transgenic mice that were engineered to overexpress human COX-2 in mammary glands developed mammary gland hyperplasia, dysplasia, and metastatic tumors (18). In a related study, transgenic mice that overexpress COX-2 in skin developed epidermal hyperplasia and dysplasia (19). Consistent with these findings, knocking out COX-2 reduced the incidence of skin papillomas and intestinal tumors (20, 21). In addition to the genetic evidence implicating COX-2 in carcinogenesis, numerous pharmacologic studies suggest that COX-2 is a therapeutic target. Selective inhibitors of COX-2 reduce the formation, growth, and metastases of experimental tumors (22–29), and decrease the number of intestinal tumors in familial adenomatous polyposis patients (30). It should be stressed, however, that the antitumor effects of selective COX-2 inhibitors might reflect mechanisms in addition to inhibition of COX-2 (31–37). Hence, both COX-2-dependent and COX-2-independent mechanisms may contribute to the antitumor activity of selective COX-2 inhibitors.
Numerous investigators have evaluated the expression of COX-2 in human prostate cancer with conflicting results. Several studies have suggested that COX-2 is commonly overexpressed in prostate cancer (38–41). In contrast, others have found that levels of COX-2 are extremely low or absent in the majority of prostate cancers (42, 43). Importantly, even if COX-2 overexpression proves to be uncommon in prostate cancer, selective COX-2 inhibitors could still be active agents if the COX-2-independent effects are clinically important.
The main purpose of the present study was to investigate whether selective COX-2 inhibitors exhibit COX-2-independent antitumor properties. Androgen-insensitive (PC3) and androgen-responsive (LNCaP) human prostate cancer cell lines were evaluated because neither cell line expressed COX-2. Clinically achievable concentrations (2.5-5.0 µmol/L) of celecoxib, a selective COX-2 inhibitor, suppressed the growth of both cell lines (44, 45). In contrast, treatment with rofecoxib, a more potent selective COX-2 inhibitor, had no effect on cell growth over the same concentration range. Notably, celecoxib also caused dose-dependent inhibition of PC3 xenograft growth. In both in vitro and in vivo studies, celecoxib suppressed cyclin D1 levels. Taken together, these findings strongly suggest that celecoxib possesses significant COX-2-independent antitumor properties and could be active even in malignancies that do not express significant amounts of COX-2 in tumor cells.
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MATERIALS AND METHODS |
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Cell Culture. PC3 and LNCaP prostate cancer cell lines were cultured in RPMI 1640 supplemented with 10% fetal bovine serum, 100 IU/mL penicillin, and 100 µg/mL streptomycin at 37°C in a humidified 5% CO2 incubator. All treatments with celecoxib, rofecoxib, or vehicle (0.1% Me2SO/DMSO) were done in the presence of 10% fetal bovine serum. Cellular cytotoxicity was assessed by measurements of lactate dehydrogenase release and trypan blue exclusion. There was no evidence of toxicity in any of our experiments.
Western Blotting. Cell lysates were prepared by treating cells with lysis buffer (Cell Signaling Technology, Inc., Beverly, MA) supplemented with 1 mmol/L phenylmethylsulfonyl fluoride, 10 µg/mL aprotinin, 10 µg/mL trypsin inhibitor, and 10 µg/mL leupeptin. Lysates were sonicated for 20 seconds on ice and centrifuged at 10,000 x g for 10 minutes to sediment particulate material. The protein concentration of the supernatant was measured by the method of Lowry et al. (46). SDS-PAGE was done under reducing conditions on 10% polyacrylamide gels as described by Laemmli (47). The resolved proteins were transferred onto nitrocellulose sheets as detailed by Towbin et al. (48). The nitrocellulose membrane was then incubated with primary antibodies. Secondary antibody to IgG conjugated to horseradish peroxidase was used. The blots were probed with enhanced chemiluminescence Western blot detection system according to the manufacturer's instructions.
Prostaglandin E2 Production in Cell Culture. One thousand cells per well were plated in 96-well dishes and allowed to attach before treatment. Amounts of PGE2 released by cells were measured by enzyme immunoassay according to the manufacturer's instructions. Production of PGE2 was normalized to cellular protein concentrations.
Cell Growth. PC3 cells (1 x 103 cells/well) and LNCaP cells (2 x 103 cells/well) were plated in 96-well plates. Cells were allowed to adhere and then treated with vehicle or selective COX-2 inhibitor. After treatment, the culture medium was removed and replaced with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (0.5 mg/mL). The reaction was stopped 4 hours later by removing medium and the formazan salt was allowed to dry. It was solubilized by adding 100 µL Me2SO and the absorbance measured at 560 nm in a 96-well plate reader.
Flow Cytometry for Cell Cycle Analysis. PC3 cells were treated with vehicle or 5.0 µmol/L celecoxib for 48 hours. Subsequently, the medium was replaced with fresh medium containing vehicle or celecoxib. After a total of 96 hours of treatment, the cells were released by treatment with trypsin-EDTA, washed and suspended in serum-free medium, counted, and then fixed overnight in 50% ethanol at 4°C. The cells (106 cells/mL) were then washed and resuspended in PBS (pH 7.4), 0.1% Triton X-100, 0.05 mg/mL DNase-free RNase A, and 50 µg/mL propridium iodide before being maintained in the dark for 30 minutes at room temperature. The red fluorescence of single events was recorded using an argon ion laser at 488 nm excitation wavelength and 610 nm emission wavelength to measure DNA index on a flow cytometer (Coulter Epics XL flow cytometer, Hialeah, FL). The percentage of cells present in each phase of the cell cycle was determined using ModFIT software (Verity Software House, Topsham, ME).
DNA Synthesis Assay. Incorporation of [3H]thymidine was used to measure DNA synthesis. Cells were plated at 1 x 103 cells/well in a 96-well plate and allowed to adhere overnight before being treated with vehicle or celecoxib for 24 hours at 37°C. Subsequently, the medium was replaced with fresh medium containing vehicle or celecoxib supplemented with [3H]thymidine (0.1 µCi/well) for 6 hours. Cells were then washed thrice with PBS. Radioactivity was then measured with a Beckman LS6800 liquid scintillation counter (Beckman, Fullerton, CA).
PC3 Xenografts. PC3 cells (1 x 106) suspended in 50% Matrigel were implanted s.c. in the flanks of 8-week-old athymic male nude mice. Six days after tumor cell inoculation, small tumors were identified. The mice were randomly distributed to each of four groups (n = 12 mice/group): control diet (AIN-76A; Research Diets, Inc., New Brunswick, NJ) or control diet supplemented with three different doses of celecoxib (150, 450, and 750 ppm). Mice were treated with these different diets for the remainder of the experiment. Tumor growth was assessed twice a week by caliper measurement of tumor diameter in the longest dimension (L) and at right angles to that axis (W). Tumor volume was estimated by the formula L x W x W x 
/6. At the time of sacrifice, plasma was prepared from blood collected by cardiac puncture. Tumors were excised and a portion fixed in 10% buffered formalin for 24 hours for immunohistochemical studies. A second portion of tumor was snap frozen and stored at –80°C for measurements of PGE2 and immunoblot analysis. The animal protocol was approved by the Institutional Animal Care and Use Committee of Weill Medical College of Cornell University.
Determination of Prostaglandin E2 in Tumor Tissues. Approximately 50 mg of frozen tissue was ground to a fine powder using a liquid-nitrogen-cooled mortar (Fisher Scientific Co., Fair Lawn, NJ). The samples were then transferred to microcentrifuge tubes and three volumes of ice-cold PBS buffer (containing 0.1% butylated hydroxytoluene and 1 mmol/L EDTA) were added before further homogenization of the sample on ice using a Knotes pellet pestle (Fisher). An aliquot (100 µL) of homogenate was transferred to a glass tube (13 x 100 mm) and subjected to extraction of PGs using a method modified after Kempen et al. (49). Briefly, 20 µL citric acid (1 N) and 2.5 µL butylated hydroxytoluene (10%) were added to samples to prevent free radical peroxidation. Before the extraction, 10 µL deuterated PGE2 (100 ng/mL) were added to each sample as an internal standard. PGs were then extracted with 1 mL of hexane/ethyl acetate (1:1, v/v) and vortex mixed for 2 minutes. Samples were centrifuged at 1,800 x g for 10 minutes at 4°C. The upper organic layer was collected and the organic phases from three extractions were pooled and then evaporated to dryness under a stream of nitrogen at room temperature. All extraction procedures were done at minimum light levels and under cold (4°C) conditions. Samples were then reconstituted in 100 µL methanol:10 mmol/L ammonium acetate buffer (pH 8.5, 70:30, v/v) before liquid chromatography-tandem mass spectrometry analysis. The protein concentration was determined by the method of Bradford (Bio-Rad, Hercules, CA).
Liquid chromatography-tandem mass spectrometry analyses were done using a Quattro Ultima tandem mass spectrometer (Micromass, Beverly, MA) equipped with an Agilent HP 1100 binary pump high-performance liquid chromatography inlet. PGs were separated using Luna 3 µm phenyl-hexyl 2 x 150 mm (Phenomenex, Torrance, CA). The mobile phase consisted of 10 mmol/L ammonium acetate (pH 8.5; phase A) and methanol (phase B). Flow rate was 250 µL/min with column temperature maintained at 50°C. Sample injection volume was 25 µL. Samples were kept at 4°C during the analysis. PGE2 was detected using electrospray negative ionization and multiple reaction monitoring the transitions at m/z 351 to 271 for PGE2 and m/z 355 to 275 for d4-PGE2. Fragmentation for these compounds was done using argon as the collision gas at a collision cell pressure of 2.10 x 10–3 Torr. The results were expressed as picograms of PGE2 per milligram protein.
Determination of Celecoxib Levels in Mouse Plasma by Liquid Chromatography-Tandem Mass Spectrometry. One hundred microliters of plasma were diluted with an equal volume of 10 mmol/L ammonium acetate (pH 8.5). To this solution, 4 mL hexane/ethyl acetate (1:1, v/v) were added; the mixture was vortex mixed for 5 minutes and then centrifuged at 4,000 rpm at 5°C for 5 minutes. The extraction was repeated twice and the upper organic layer was collected, pooled, and evaporated to dryness under a stream of nitrogen at room temperature under reduced room light conditions to limit the possibility of photooxidation. The sample was then reconstituted in 200 µL of methanol:10 mmol/L ammonium acetate (pH 8.5, 1:1, v/v). The celecoxib level in the samples was determined by liquid chromatography-tandem mass spectrometry.
Liquid chromatography-tandem mass spectrometry was operated under the same condition as described above for PGE2 analysis with minor changes. Briefly, 10 µL of the sample was injected on a Luna 3 µm phenyl-hexyl 2 x 150 mm analytic column (Phenomenex). Celecoxib was detected and quantified by operating the mass spectrometer in electrospray negative ion mode and monitoring the transition m/z 380.2 > 316.1. Quantification was done by comparing the sample peak areas to a standard curve constructed from peak areas of extracted plasma sample added to known amounts of celecoxib.
Immunohistochemistry. Proliferation and angiogenesis were evaluated by staining for Ki-67 and CD34 as described previously (50, 51) . Neutral buffered formalin-fixed tissue was embedded in paraffin. Tissue sections (5 µm) were prepared using a microtome and mounted on slides. Immunohistochemical analysis was done within 24 hours of the sections being cut. Sections were deparaffinized in xylene, rehydrated in graded alcohols, and washed in distilled water. Endogenous peroxidase activity was quenched with 0.01% H2O2. Antigen retrieval was done by microwaving the sections in 10 mmol/L citric acid (pH 6.0) for 30 minutes. In addition, sections for Ki-67 analysis were treated with 0.05% trypsin, 0.05% CaCl2 in Tris-HCl (pH 7.6) for 5 minutes at 37°C before microwave treatment. The slides were washed thrice in PBS and blocked for 30 minutes with 10% normal rabbit serum (CD34) or 10% normal horse serum (Ki-67). Tissue sections were then incubated with antiserum to mouse CD34 at 25 µg/mL and antiserum to Ki-67 at a 1:5,000 dilution (2% bovine serum albumin in PBS) and incubated overnight at 4°C. After being washed thrice with PBS, the sections were incubated with biotinylated anti-mouse immunoglobulins at 1:100 (CD34) or 1:500 (Ki-67; Vector Laboratories) dilution for 30 minutes at room temperature. The slides were then washed thrice in PBS and labeled using 1:25 avidin-biotin peroxidase complexes (Vector Stain) for 30 minutes at room temperature. The reaction was visualized using 3,3-diaminobenzidine. Subsequently, the slides were rinsed in tap water and counterstained with hematoxylin. The slides were then dehydrated with ethanol, rinsed with xylene, and mounted.
Proliferation was assessed by counting the number of Ki-67 positively staining nuclei and total number of cancer cells at x400 magnification, in three representative regions of the tumor. Results are expressed as the proportion of positively staining cells over the total number of cells. Microvessel density was assessed by counting the number of microvessels at x200 magnification in three fields that had the highest vascularization. The results are expressed as an average number of microvessels per field.
Statistics. Xenograft tumor growth was compared between dosage groups by fitting a quadratic curve to the log tumor volume from days 9 to 30 for each mouse. The linear and quadratic coefficients were then compared jointly using repeated measures ANOVA to test overall dose effect and pair-wise contrasts between successive doses. Results are expressed descriptively as the mean ± SE. All other comparisons between groups were made by the two-tailed Student's t test with results presented as the mean ± SD. A difference between groups of P < 0.05 was considered significant.
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RESULTS |
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DISCUSSION |
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Initially, we found that COX-2 was not expressed in either PC3 or LNCaP cells. This conclusion was based on the results of immunoblotting, Northern blot analysis, and the inability to suppress PGE2 biosynthesis with two different selective COX-2 inhibitors. Although the absence of COX-2 in these cell lines agrees with some reports (42, 52), other investigators have detected COX-2 in PC3 cells (34, 53). This apparent difference is likely to reflect the use of different clones by different laboratories. It is noteworthy that clinically achievable concentrations of celecoxib (44, 45) suppressed the growth of both PC3 and LNCaP cell lines whereas rofecoxib had no effect over the same concentration range. Because COX-2 is not expressed in these two cell lines, the growth inhibitory effect of celecoxib must reflect a COX-2-independent mechanism. Although other studies have suggested that selective COX-2 inhibitors including celecoxib possess COX-2-independent activity (31–37), the significance of this work has been questioned because extremely high concentrations of drug were used (31, 54, 55). To our knowledge, this is the first study to show that a selective COX-2 inhibitor has COX-2-independent antitumor properties using a concentration of drug that is clinically achievable (44, 45).
To further investigate the mechanism underlying the growth inhibitory effects of celecoxib, flow cytometry was done. Celecoxib caused an accumulation of cells in G0-G1 and a corresponding decrease in S phase. Similar effects of celecoxib have been observed in rat prostate cancer cells (56). Consistent with these results, a dose-dependent decrease in [3H]thymidine incorporation was observed in our study. Changes in cyclin D1 expression impact on the progression of cells from G1 to S. Hence, the discovery that treatment with celecoxib caused a significant reduction in amounts of cyclin D1 is significant.
We next used an experimental model of prostate cancer to attempt to translate these in vitro findings. Treatment with celecoxib caused a dose-dependent decrease in the growth of PC3 xenografts. To better understand the growth inhibitory effects of celecoxib, measurements of microvessel density and cell proliferation were done. Treatment with celecoxib caused nearly a 50% decrease in both microvessel density and cell proliferation. These findings are consistent with prior evidence that selective COX-2 inhibitors can suppress the growth of transplantable tumors by inhibiting angiogenesis and cell proliferation (26, 28, 57–60). Although celecoxib inhibited the growth of cultured PC3 cells by a COX-2-independent mechanism, we acknowledge that our in vivo findings do not allow us to exclude a COX-2-dependent growth inhibitory effect. Because COX-2 is expressed in neovasculature (58), celecoxib may have inhibited tumor growth at least, in part, by a COX-2-dependent antiangiogenic mechanism. Because the vasculature comprises a relatively small proportion of the xenograft, celecoxib may have suppressed tumor growth by inhibiting angiogenesis without causing a decrease in intratumor PGE2. Based on our in vitro findings, levels of cyclin D1 were measured in tumor samples. Similar to what was observed in cultured PC3 cells, celecoxib caused a reduction in amounts of cyclin D1 in PC3 xenografts. This finding is consistent with previous evidence that a selective COX-2 inhibitor suppressed levels of cyclin D1 in an experimental model of colorectal carcinoma (29). Importantly, the suppressive effects that we observed occurred at plasma concentrations of celecoxib that were essentially identical to the doses required to induce COX-2-independent changes in vitro. Thus, it remains uncertain if the observed decrease in tumor cell proliferation in PC3 xenografts is a consequence of reduced angiogenesis, a COX-2-independent growth inhibitory effect of celecoxib as observed in vitro, or a combination of both mechanisms.
In summary, our in vitro studies show that clinically achievable concentrations of celecoxib inhibit the growth of prostate cancer cells by a COX-2-independent mechanism. Moreover, the discovery that celecoxib and rofecoxib have different COX-2-independent effects raises the possibility that the antitumor activity of selective COX-2 inhibitors could differ. Currently, the dose of selective COX-2 inhibitor used in chemoprevention and cancer treatment studies is based on the amount of drug required to inhibit COX-2 activity (61). Whether different doses will be required to optimize the COX-2-independent effects and therefore the antitumor activity of these drugs should be explored. We emphasize that the results of this study do not detract from the substantial body of evidence indicating that COX-2 is a rational target for anticancer therapy. Our study does suggest, however, that COX-2-independent effects may also be important for understanding the overall antitumor activity of selective COX-2 inhibitors.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 9/13/04; revised 10/25/04; accepted 10/26/04.
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REFERENCES |
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and phorbol ester. J Clin Invest 1994;93:493–8.
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S. M. Lippman and J. J. Lee Reducing the "Risk" of Chemoprevention: Defining and Targeting High Risk--2005 AACR Cancer Research and Prevention Foundation Award Lecture. Cancer Res., March 15, 2006; 66(6): 2893 - 2903. [Abstract] [Full Text] [PDF]
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S. I. Mohammed, D. Dhawan, S. Abraham, P. W. Snyder, D. J. Waters, B. A. Craig, M. Lu, L. Wu, R. Zheng, J. Stewart, et al. Cyclooxygenase inhibitors in urinary bladder cancer: in vitro and in vivo effects. Mol. Cancer Ther., February 1, 2006; 5(2): 329 - 336. [Abstract] [Full Text] [PDF]
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L. R. Howe, S.-H. Chang, K. C. Tolle, R. Dillon, L. J.T. Young, R. D. Cardiff, R. A. Newman, P. Yang, H. T. Thaler, W. J. Muller, et al. HER2/neu-Induced Mammary Tumorigenesis and Angiogenesis Are Reduced in Cyclooxygenase-2 Knockout Mice Cancer Res., November 1, 2005; 65(21): 10113 - 10119. [Abstract] [Full Text] [PDF]
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A. Ferrario, A. M. Fisher, N. Rucker, and C. J. Gomer Celecoxib and NS-398 Enhance Photodynamic Therapy by Increasing In vitro Apoptosis and Decreasing In vivo Inflammatory and Angiogenic Factors Cancer Res., October 15, 2005; 65(20): 9473 - 9478. [Abstract] [Full Text] [PDF]
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 M. Hermann, H. Krum, and F. Ruschitzka To the Heart of the Matter: Coxibs, Smoking, and Cardiovascular Risk Circulation, August 16, 2005; 112(7): 941 - 945. [Full Text] [PDF]
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 C. Mascaux, B. Martin, J-M. Verdebout, V. Ninane, and J-P. Sculier COX-2 expression during early lung squamous cell carcinoma oncogenesis Eur. Respir. J., August 1, 2005; 26(2): 198 - 203. [Abstract] [Full Text] [PDF]
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