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DNA oxidation induced by cyclooxygenase-2
1Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612-7231, USA.
Abstract:
The inducible form of cyclooxygenase, COX-2, has been shown to be overexpressed in various types of tumors, including colon and prostate cancer. Several studies indicate that COX-2 inhibition can be beneficial for the prevention of these types of cancer. Since COX-2 reactions involve production of reactive oxygen radicals that can potentially damage biological macromolecules, we explored the possibility that DNA and/or nucleosides can be oxidized during cyclooxygenase reactions. When DNA or nucleosides were incubated with COX-2 and arachidonic acid, a significant increase in the amount of 8-oxo-2'-deoxyguanosine was observed. This increase was enzyme-dependent and could be prevented by COX-2 inhibitors as well as by antioxidants. These data indicate that peroxyl radicals or other oxidized species formed during conversion of arachidonic acid to prostaglandin G(2) might be responsible for the observed oxidation. These results suggest also that overexpression of COX-2 in inflammatory diseases places an additional burden on antioxidative defenses of the cell, which might contribute to DNA oxidation and the induction of mutations.
Insights
Cyclooxygenase-2 (COX-2) overexpression in tumors may cause DNA oxidation via reactive oxygen species. Inhibiting COX-2 or using antioxidants can prevent this damage, suggesting a role in cancer prevention.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- The inducible cyclooxygenase, COX-2, is overexpressed in various cancers, including colon and prostate.
- COX-2 inhibition shows potential for cancer prevention.
- COX-2 reactions generate reactive oxygen radicals, potentially damaging macromolecules.
Purpose of the Study:
- To investigate if DNA and nucleosides are oxidized during cyclooxygenase reactions.
- To determine the role of COX-2 in DNA oxidation.
Main Methods:
- Incubation of DNA or nucleosides with COX-2 and arachidonic acid.
- Measurement of 8-oxo-2'-deoxyguanosine as a marker of DNA oxidation.
- Testing the effects of COX-2 inhibitors and antioxidants.
Main Results:
- A significant increase in 8-oxo-2'-deoxyguanosine was observed when DNA/nucleosides were incubated with COX-2 and arachidonic acid.
- The oxidation was enzyme-dependent and could be blocked by COX-2 inhibitors and antioxidants.
- Peroxyl radicals or other oxidized species formed during arachidonic acid conversion are likely responsible.
Conclusions:
- COX-2 activity can lead to DNA oxidation.
- Overexpression of COX-2 in inflammatory conditions may increase DNA damage and mutation risk.
- COX-2 inhibition and antioxidant use could be strategies for cancer prevention by mitigating DNA oxidation.