Cyclooxygenase-2 inhibitor nimesulide blocks ultraviolet B-induced photocarcinogenesis in SKH-1 hairless mice.

Abstract

Cyclooxygenase-2 (COX-2) inhibition can inhibit UVB-induced carcinogenesis in the skin. We have shown that COX-2 is overexpressed in UVB-induced squamous cell carcinomas (SCCs). Celecoxib, a specific inhibitor of COX-2, blocks UVB-induced papillomas and carcinomas in murine skin. However, as COX-2 inhibitors of this type are associated with an increased risk of adverse cardiovascular events, we decided to study nimesulide, a different class of COX-2 inhibitor, an N-arylmethanesulfonamide derivative not known to have these untoward effects. To assess the antitumor-promoting effects of nimesulide, 90 mice were equally divided into three groups. Group I animals received no test agent or UVB and served as age-matched controls; group II animals were irradiated with UVB (180 mJ cm(-2), twice weekly for 35 weeks) and group III animals received 300 p.p.m. nimesulide in drinking water and were irradiated with UVB as described for group-II. Nimesulide treatment reduced the growth of UVB-induced tumors both in terms of tumor number and tumor volume. By weeks 25, 30 and 35, the tumor numbers in the nimesulide-treated group were 79%, 49% and 53% less than the number occurring in UVB-treated animals whereas tumor volume was reduced 69%, 54% and 53%, respectively, compared to the UVB-irradiated control group. Nimesulide also inhibited the malignant progression of SCCs. The reduction in tumorigenesis was paralleled by a decrease in cell cycle regulatory proteins (cyclins A, B1, D1, E, CDK2/4/6) and the antiapoptotic protein (Bcl2); concomitantly there was an increase in proapoptotic markers, poly (ADP-ribose) polymerase (PARP) and caspase-3. Nimesulide also decreased ornithine decarboxylase expression and the nuclear accumulation of nuclear factor kappa B transcriptionally active protein complexes. These results show that alternative classes of COX-2 inhibitors may likely be efficacious as cancer chemopreventive agents and may have an improved therapeutic index.

• Authors: Xiuwei Tang, Arianna L Kim, Levy Kopelovich, David R Bickers, Mohammad Athar
• Journal: Photochemistry and photobiology (Photochem Photobiol) 2008 Mar-Apr Vol. 84 Issue 2 Pg. 522-7 ISSN: 0031-8655 [Print] United States
• PMID: 18266822 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cyclooxygenase Inhibitors
• Sulfonamides
• Cyclooxygenase 2
• nimesulide

Topics

• Animals
• Cyclooxygenase 2 (drug effects)
• Cyclooxygenase Inhibitors (pharmacology)
• Female
• Mice
• Mice, Hairless
• Neoplasms, Radiation-Induced (prevention & control)
• Skin Neoplasms (prevention & control)
• Sulfonamides (pharmacology)
• Ultraviolet Rays