Molecular mechanisms involved in the antiproliferative effect of two COX-2 inhibitors, nimesulide and NS-398, on colorectal cancer cell lines

Background. Cyclooxygenase (COX)-2 is up-regulated in most colorectal cancers. Chronic use of non-steroidal anti-inflammatory drugs, which target cyclooxygenases, have been shown to reduce the risk of these cancers. However, the mechanisms underlying this protective effect remain unclear. Aims. The aim of our study was to characterize the effects of two COX-2 selective inhibitors, NS-398 and nimesulide, on colorectal cancer cell proliferation, and to describe the molecular mechanisms involved. Materials and methods. HT-29 and SW-1116 cell lines were cultured with either NS-398 or nimesulide. Cell proliferation was assessed by staining DNA with crystal violet. Cell cycle repartition and apoptosis were analysed by flow cytometry. The expression of COX-1 and COX-2, and of two cyclin dependent kinase inhibitors, p21(Cip1) and p27(Kip1), was analysed by Western blotting and RT-PCR. Results. Both drugs dose-dependently inhibited cell proliferation and induced G1 cell cycle blockade. HT-29 cells were more sensitive to both drugs than SW-1116 cells. p21(Cip1) and p27(Kip1) were induced on both cell lines. Concomitant induction of p21(Cip1) mRNA indicates transcriptional modulation, whereas induction of p27(Kip1) only at the protein level suggests post-translational modulation. Conclusion. NS-398 and nimesulide inhibit colorectal cell proliferation through induction of p21(Cip1) and p27(Kip1). (C) 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.