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Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?

Ostrowski J, Wocial T, Skurzak H, Bartnik W - Br. J. Cancer (2003)

Bottom Line: An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness.Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis.The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Medical Center for Postgraduate Education, Warsaw, Poland. jostrow@warman.com.pl

ABSTRACT
Two isoforms of cyclooxygenase (COX) participate in growth control; COX-1 is constitutively expressed in most cells, and COX-2 is an inducible enzyme in response to cellular stimuli. An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness. Although both COX-1 and COX-2 inhibitors are suppressors of cell proliferation and appear to be chemopreventive agents for tumorigenesis, the molecular mechanisms mediating antiproliferative effect of COX inhibitors are still not well defined. This study contrasts and compares the effects of aspirin and celecoxib, inhibitors of COX-1 and COX-2, in rat hepatoma HTC-IR cells. The following were assessed: cell proliferation and apoptosis, ornithine decarboxylase (ODC) activity, and pattern expression of three immediate-early genes, c-myc, Egr-1, and c-fos. We have shown that the treatment of hepatocytes in vitro with the selective COX-2 inhibitor, celecoxib, was associated with induction of apoptosis and complete inhibition of cellular proliferation. Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis. Treatment with celecoxib produced dose- and time-dependent decrease in ODC activity. In addition, at higher drug concentration the decrease in ODC activity was greater in proliferating than in resting cells. Much lesser inhibitory effect on ODC activity was observed in aspirin-treated cells. The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA. Our study revealed that celecoxib and aspirin share the ability to inhibit ODC activity and alter the pattern of immediate-early gene expression. It seems that some of the observed effects are likely to be related to COX-independent pathways. The precise mechanisms of action of COX inhibitors should be defined before using these drugs for cancer chemopreventive therapy.

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The effect of aspirin on ODC activity. Proliferating or resting HTC-IR cells were treated with aspirin at concentration 5 μg ml−1 (A) or 50 μg ml−1 (B). The cells were harvested at different time points and ODC activity was determined. The results are expressed as percentage of ODC activity in control cells treated with vehicle (0.1% DMSO) and represent means±s.d. of three separate experiments. a indicates significant decrease (a, P<0.05) in enzyme activity in aspirin-treated cells compared to cells treated with DMSO.
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fig7: The effect of aspirin on ODC activity. Proliferating or resting HTC-IR cells were treated with aspirin at concentration 5 μg ml−1 (A) or 50 μg ml−1 (B). The cells were harvested at different time points and ODC activity was determined. The results are expressed as percentage of ODC activity in control cells treated with vehicle (0.1% DMSO) and represent means±s.d. of three separate experiments. a indicates significant decrease (a, P<0.05) in enzyme activity in aspirin-treated cells compared to cells treated with DMSO.

Mentions: The effect of celecoxib on ODC activity. The HTC-IR cells were plated at 5 × 106 per plastic cell culture flask and were grown for 24 h. Proliferating or resting (serum-starved) cells were treated with celecoxib at concentration 5 μg ml−1 (A) or 50 μg ml−1 (B) for 0, 0.5, 1, 2, 6, and 24 h. Then the cells were harvested and ODC activity was determined. The effects of the treatment are expressed as percentage of ODC activity in control cells treated with vehicle (0.1% DMSO) and represent means±s.d. of three separate experiments. a, b, c indicate significant decrease (a, P<0.05; b, P<0.01; c, P<0.001) in enzyme activity in aspirin-treated cells compared to cells treated with DMSO. P<0.05 indicates significant differences in ODC activity between fasting and proliferating cells.


Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?

Ostrowski J, Wocial T, Skurzak H, Bartnik W - Br. J. Cancer (2003)

The effect of aspirin on ODC activity. Proliferating or resting HTC-IR cells were treated with aspirin at concentration 5 μg ml−1 (A) or 50 μg ml−1 (B). The cells were harvested at different time points and ODC activity was determined. The results are expressed as percentage of ODC activity in control cells treated with vehicle (0.1% DMSO) and represent means±s.d. of three separate experiments. a indicates significant decrease (a, P<0.05) in enzyme activity in aspirin-treated cells compared to cells treated with DMSO.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376368&req=5

fig7: The effect of aspirin on ODC activity. Proliferating or resting HTC-IR cells were treated with aspirin at concentration 5 μg ml−1 (A) or 50 μg ml−1 (B). The cells were harvested at different time points and ODC activity was determined. The results are expressed as percentage of ODC activity in control cells treated with vehicle (0.1% DMSO) and represent means±s.d. of three separate experiments. a indicates significant decrease (a, P<0.05) in enzyme activity in aspirin-treated cells compared to cells treated with DMSO.
Mentions: The effect of celecoxib on ODC activity. The HTC-IR cells were plated at 5 × 106 per plastic cell culture flask and were grown for 24 h. Proliferating or resting (serum-starved) cells were treated with celecoxib at concentration 5 μg ml−1 (A) or 50 μg ml−1 (B) for 0, 0.5, 1, 2, 6, and 24 h. Then the cells were harvested and ODC activity was determined. The effects of the treatment are expressed as percentage of ODC activity in control cells treated with vehicle (0.1% DMSO) and represent means±s.d. of three separate experiments. a, b, c indicate significant decrease (a, P<0.05; b, P<0.01; c, P<0.001) in enzyme activity in aspirin-treated cells compared to cells treated with DMSO. P<0.05 indicates significant differences in ODC activity between fasting and proliferating cells.

Bottom Line: An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness.Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis.The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Medical Center for Postgraduate Education, Warsaw, Poland. jostrow@warman.com.pl

ABSTRACT
Two isoforms of cyclooxygenase (COX) participate in growth control; COX-1 is constitutively expressed in most cells, and COX-2 is an inducible enzyme in response to cellular stimuli. An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness. Although both COX-1 and COX-2 inhibitors are suppressors of cell proliferation and appear to be chemopreventive agents for tumorigenesis, the molecular mechanisms mediating antiproliferative effect of COX inhibitors are still not well defined. This study contrasts and compares the effects of aspirin and celecoxib, inhibitors of COX-1 and COX-2, in rat hepatoma HTC-IR cells. The following were assessed: cell proliferation and apoptosis, ornithine decarboxylase (ODC) activity, and pattern expression of three immediate-early genes, c-myc, Egr-1, and c-fos. We have shown that the treatment of hepatocytes in vitro with the selective COX-2 inhibitor, celecoxib, was associated with induction of apoptosis and complete inhibition of cellular proliferation. Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis. Treatment with celecoxib produced dose- and time-dependent decrease in ODC activity. In addition, at higher drug concentration the decrease in ODC activity was greater in proliferating than in resting cells. Much lesser inhibitory effect on ODC activity was observed in aspirin-treated cells. The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA. Our study revealed that celecoxib and aspirin share the ability to inhibit ODC activity and alter the pattern of immediate-early gene expression. It seems that some of the observed effects are likely to be related to COX-independent pathways. The precise mechanisms of action of COX inhibitors should be defined before using these drugs for cancer chemopreventive therapy.

Show MeSH
Related in: MedlinePlus