PC‐407, a celecoxib derivative, inhibited the growth of colorectal tumor in vitro and in vivo

Abstract

This study aimed to observe the growth-inhibitory effect of PC-407 (4-[5-naphthyl-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide), a celecoxib derivative synthesized in our lab, in human colorectal cancer cells and a colitis-associated colorectal cancer (CACC) model, and investigate the relative molecular mechanisms. SW-1116 (expressing a high level of cyclooxygenase-2 [COX-2]), HT-29 (expressing a moderate level of COX-2), and SW-480 (no expression of COX-2) cell lines were exposed to different concentrations of celecoxib (0-100 micromol/L) or PC-407 (0-100 micromol/L). Then, COX-2 levels were assessed by reverse transcription-PCR and Western blotting. COX-2 activity was evaluated by measuring prostaglandin E(2) concentration using enzyme-linked immunoassay. A mouse model of colitis-associated carcinogenesis was employed to determine the effect of PC-407 in vivo. PC-407 inhibited cell growth in a concentration-dependent manner, and the IC(50) values of PC-407 for growth inhibition of SW-1116, HT-29, and SW-480 cells were 17.60 +/- 3.02, 18.14 +/- 2.81, and 8.13 +/- 0.40 micromol/L, respectively. PC-407 down-regulated COX-2 mRNA and protein levels and reduced prostaglandin E(2) production significantly. In vivo, PC-407 inhibited the genesis of CACC effectively. Our data indicate that PC-407 can inhibit the growth of tumor both in vitro and in vivo and suggest that the effect probably involves inhibition of the COX-2 pathway and other COX-2-independent pathways.