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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online October 15, 2001 as doi:10.1096/fj.01-0299fje. |
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pharmazentrum frankfurt, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, 60590 Frankfurt am Main, Germany
2Correspondence: Institut für klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. E-mail: geisslinger{at}em.uni-frankfurt.de
SPECIFIC AIMS
The chronic use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the risk of colon cancer. Recently, a similar protective effect has been demonstrated for the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib, which has been approved by the FDA to reduce the number of adenomatous colorectal polyps in patients with familial adenomatous polyposis (FAP). The exact mechanisms that account for the anti-proliferative effects of celecoxib and other NSAIDs are still not fully understood, and it is still controversial whether or not these effects are mediated predominantly through the inhibition of COX-2 activity and prostaglandin synthesis. Since a dependence on COX-2 activity would imply that the effects occur mainly in COX-2 overexpressing but not in COX-2-deficient tumors, this question is of considerable clinical importance.
To answer this question, we assessed the effects of the selective COX-2 inhibitor celecoxib and the selective COX-1 inhibitor SC560 on colon cancer cell growth in vitro and in vivo using different colon cancer cell lines that either express COX-2 (HT-29 and Caco-2) or are COX-2 deficient (HCT-15).
PRINCIPAL FINDINGS
1. Celecoxib and SC560 affected cell survival and induced apoptosis in colon carcinoma cell lines irrespective of their COX-2 status
To evaluate whether the expression of COX-2 determined the sensitivity toward the selective COX-2 inhibitor celecoxib or the selective COX-1 inhibitor SC560, we assessed the survival of the different cell lines in the colony-forming assay. Celecoxib and SC560 inhibited cell survival of the COX-2-expressing HT-29 and Caco-2 cells (IC50 celecoxib 11.4 µM and 26.5 µM, respectively; IC50 SC560 18.6 µM and 12.4 µM, respectively) as well as COX-2-deficient HCT-15 cells (IC50 celecoxib 22.2 µM and IC50 SC560 25.7 µM) with no obvious relationship between the observed cytotoxicity and COX-2 protein expression. To explore potential mechanisms for the observed cell killing, we assessed whether the drugs induced apoptosis. Hence, we investigated DNA and PARP (poly-ADP-ribose polymerase) cleavage and the occurrence of cells in the sub-G1 phase. DNA fragmentation was assessed by measuring mono- and oligonucleosomes using a commercially available enzyme immunoassay kit. Celecoxib caused DNA cleavage in each cell line (at 50–100 µM). HT-29 cells were most sensitive. Conversely, SC560 (up to 100 µM) had no effect in any of the cell lines used.
PARP cleavage was assessed by Western blot analysis. It occurred with celecoxib (100 µM) in each cell line tested. SC560 (100 µM) had no effect.
We determined the percentage of cells in the sub-G1 phase using flow cytometry. Celecoxib (100 µM) caused a clear increase of the sub-G1 fraction in each cell line (Fig. 1
A–C). SC560 (100 µM) caused only a slight increase of the sub-G1 fraction. The results of these ‘apoptosis tests’ indicate that celecoxib causes apoptotic cell death in different colon cancer cell lines irrespective of the COX-2 expression of the cells.
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2. Celecoxib and, to a lesser extent, SC560 induced a G0/G1 cell cycle arrest in three different colon cancer cell lines irrespective of whether the cells expressed COX-2
Since apoptosis often occurs in consequence of a cell cycle block, we checked whether the observed cytotoxicity of celecoxib and SC560 was mediated by an alteration of the cell division cycle. Cell cycle distribution was assessed using flow cytometry. Cultures were synchronized by incubation in FCS-free medium for 48 h. HCT-15, Caco-2 and HT-29 cells were then treated with increasing concentrations (25, 50, 75, 100 µM) of celecoxib or SC560 for 24 h or left untreated. Treatments were added to medium supplemented with 10% FCS. Cells were harvested by trypsinization, fixed with 80% ethanol, and stained with propidium iodide.
Both drugs caused an accumulation of cells in the G0/G1 phase and thus inhibited transition to the S phase. The effects of celecoxib and SC560 occurred in all three cell lines in a concentration-dependent manner and were more pronounced with celecoxib (Fig. 1A-C
).
3. Celecoxib inhibited the G0/G1 to S phase transition by decreasing the expression of cyclins and increasing the expression of the cell cycle inhibitory proteins p21Waf1 and p27Kip1
To evaluate potential molecular mechanisms causing the cell cycle arrest, we assessed the expression of cell cycle regulatory proteins (cdk-1, cyclin A, cyclin B1, p21Waf1, and p27Kip1) by Western blot analysis. In all three cell lines, a marked time-dependent decrease in cyclin A and B1 expression was observed when cells were treated with 100 µM celecoxib. Cdk-1 protein levels also decreased, though to a lesser extent than those of both cyclins. Conversely, the expression of p21Waf1 and p27Kip1 increased in a time-dependent manner (Fig. 2
A, B) with a maximum at 24 h. This effect occurred in all three cell lines irrespective of the COX-2 status. In contrast to celecoxib, SC560 did not change the expression of the cell cycle regulatory proteins tested.
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4. Celecoxib and SC560 inhibited growth of colon cancer xenografts in nude mice
In nude mice, celecoxib (10 and 100 mg/kg/day) and SC560 (10 and 100 mg/kg/day) significantly inhibited the growth of HCT-15 colon cancer xenografts, which are COX-2 deficient. However, celecoxib (up to 25 mg/kg/day) and SC560 (up to 100 mg/kg/day) had no significant effect on HT-29 tumors that express COX-2. This further supports the hypothesis that the anti-proliferative effects of celecoxib are not solely mediated through an inhibition of COX-2 activity. Plasma concentrations in nude mice of celecoxib were in the range of 3–4 µM (100 mg/kg) and thus were similar to those found in humans after a single oral dose of 800 mg (3–5 µM) (2x400 mg is approved by the FDA for adjuvant therapy in FAP patients). For SC560, maximum plasma concentrations were 0.8 ± 0.12 µM (10 mg/kg) and 1.6 ± 0.5 µM (100 mg/kg).
CONCLUSIONS AND SIGNIFICANCE
A host of different mechanisms has been proposed to contribute to the anti-proliferative effects of aspirin and other NSAIDs including inhibition or activation of NF-
B, AP-1, MAP kinase members PPAR
and PPAR
, and alterations of cell cycle regulatory proteins such as cyclins, p21Waf1, p27Kip1, p70S6 kinase, and others. The latter effect has been demonstrated for sulindac and its metabolite sulindac sulfide in colon cancer cells for sodium salicylate in vascular endothelial cells and for NS-398 (a selective COX-2 inhibitor) in human lung cancer cells. We show in the present study that induction of apoptosis and alteration of cell cycle regulatory proteins is also a major mechanism accounting for the anti-proliferative effects of celecoxib. All of the in vitro effects were independent of whether the cells expressed COX-2, suggesting that the anti-tumor activity of celecoxib is independent of its COX-2 inhibitory properties. This is further supported by a comparison of COX-2 inhibitory and anti-proliferative concentrations, which reveal that concentrations required to inhibit tumor cell proliferation are 
4 orders of magnitude higher than those needed to inhibit COX-2 activity. The significance of these in vitro studies is emphasized by a recent human study demonstrating that celecoxib was able to reduce polyp growth in patients with FAP. The effect was statistically significant only at a rather high dose of 800 mg/daily but not at the recommended anti-inflammatory dose of 100–200 mg b.i.d. This again suggests that high concentrations of celecoxib are required for anti-proliferative effects. The plasma concentrations of celecoxib in our nude mice experiments were in the range of those found in human plasma after administration of a single 800 mg dose.
The direct cellular targets of celecoxib are still unknown. However, it is conceivable that the cell cycle block is in part a consequence of the activation of different transcription factors since cell cycle regulatory proteins such as p21Waf1, cyclin A and cyclin B are known target genes of the stress-related transcription factors p53, AP-1, or NF-B (Fig. 3
). Indeed, we have recently shown that high concentrations of celecoxib activate NF-B. Furthermore, celecoxib was reported to inhibit the activation of protein kinase B (PKB)/Akt in prostate cancer cells. This effect was associated with induction of apoptosis in these cells, suggesting that inhibition of PKB/Akt may also contribute to the anti-proliferative activity of celecoxib in certain carcinomas (Fig. 3)
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The findings of the present study contribute to our understanding of the anti-proliferative effects of celecoxib and emphasize the role of cell cycle regulatory proteins for the anti-tumor effects of NSAIDs. In addition, the use of cell lines that differ in the expression of COX-2 allows us to conclude that the effects of celecoxib are independent of its COX-2 inhibitory properties and therefore probably are not restricted to COX-2-expressing tumors.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0299fje; to cite this article, use FASEB J. (October 15, 2001) 10.1096/fj.01-0299fje 
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A. H. Schonthal, C. R. Herzog, M. V. Swamy, and C. V. Rao Correspondence re: M. V. Swamy et al., Inhibition of COX-2 in Colon Cancer Cell Lines by Celecoxib Increases the Nuclear Localization of Active p53. Cancer Res 2003;63:5239-42. Cancer Res., April 15, 2004; 64(8): 2937 - 2938. [Full Text] [PDF]
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activation; —| inhibition).