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

• Published in: Cancer science 2009-12, Vol.100 (12), p.2451-2458
• Main Authors: Li, Yuhua, Niu, Yinbo, Wu, Huanjie, Zhang, Bangle, Sun, Yang, Huang, Haitao, Li, Qian, Fan, Lei, Liu, Li, Mei, Qibing
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; beta Catenin - metabolism; Celecoxib; Cell Line, Tumor; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Cyclooxygenase 2 Inhibitors - pharmacology; HT29 Cells; Humans; Male; Mice; Mice, Inbred ICR; Naphthalenes - pharmacology; Original; Phosphorylation; Pyrazoles - pharmacology; Sulfonamides - pharmacology
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/j.1349-7006.2009.01335.x

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 μmol/L) or PC‐407 (0–100 μmol/L). Then, COX‐2 levels were assessed by reverse transcription‐PCR and Western blotting. COX‐2 activity was evaluated by measuring prostaglandin E2 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 IC50 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 μmol/L, respectively. PC‐407 down‐regulated COX‐2 mRNA and protein levels and reduced prostaglandin E2 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. (Cancer Sci 2009; 100: 2451–2458)