Preventive effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on DEN-induced hepatocarcinogenesis in rats.
BACKGROUND
Chemopreventive effect of a selective cyclooxygenase-2 (COX-2) inhibitor JTE-522 on diethylnitrosamine (DEN)-induced hepatocarcinogenesis was evaluated in Wistar rats.


METHODS
Animals in the control group (G1) were injected with phosphate buffered saline (PBS), those in hepatocellular carcinoma (HCC) group (G2) were injected with DEN with regular foods for 14 weeks, and those in the treatment groups were injected with DEN for 14 weeks fed with JTE-522 for 7 (G3) and 14 weeks (G4), respectively. Proliferation and precancerous lesions were evaluated by expression levels of proliferating cell nuclear antigen (PCNA) and glutathione S-transferase-P (GST-P), respectively by immunohistochemistry and Western blot analysis. Apoptosis and oxidative stress were evaluated by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining, respectively.


RESULTS
After 14 weeks of the treatment, HCC was developed in G2, G3, and G4 showing no significant differences in gross appearance and histology of the liver among the three groups. There were no significant differences in the expression levels of PCNA and numbers of TUNEL and 8-OHdG positive cells in the liver among the three groups. However, GST-P positive area was significantly suppressed in G3 and G4 compared to G2.


CONCLUSIONS
Our data revealed that JTE-522 had a modest inhibitory effect on hepatocarcinogenesis in rats in a manner independent of induction of apoptosis and inhibition of oxidative stress.
Nagahara
Takakazu
T
Second Department of Internal Medicine, Tottori University School of Medicine, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japan. takakazu@med.tottori-u.ac.jp
Okano
Jun-Ichi
J
Fujise
Yuki
Y
Abe
Ryo
R
Murawaki
Yoshikazu
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004052:Diethylnitrosamine / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D000096926:Benzenesulfonamides
D001557:Benzenesulfonates; D052246:Cyclooxygenase 2 Inhibitors; D004052:Diethylnitrosamine; D005982:Glutathione Transferase; D010080:Oxazoles; D018809:Proliferating Cell Nuclear Antigen; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides