Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol.
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural product occurring in grapes and various other plants with medicinal properties associated with reduced cardiovascular disease and reduced cancer risk. To evaluate the possibility and potential mechanism(s) of which resveratrol inhibits N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis, 96 F344 male rats were divided into 10 groups and resveratrol (1 and 2 mg/kg) was administered orally or intraperitoneally (i.p.). In the groups in which resveratrol was administered at 2 mg/kg (orally, for 16 weeks), 1 and 2 mg/kg (i.p., for 16 weeks) and 1 mg/kg (i.p., for 20 weeks), the number of NMBA-induced esophageal tumors per rat was significantly reduced to 78, 62, 54 and 48, respectively (P < 0.05), and the size of maximum tumors in each group with resveratrol treatment was also significantly smaller than that in NMBA alone group (P < 0.05). Although the pathological examination did not indicate significantly decreased incidence of carcinomas by administering resveratrol, the tendency of carcinogensis suppression was observed (P = 0.177). Semi-quantitative RT-PCR and ELISA analysis demonstrated that following NMBA treatment, the expression of COX-1 mRNA was strongly present in tumor tissues, while weakly present in non-tissues; the expression of COX-2 mRNA was induced in both tumor and non-tumor tissues. The production of prostaglandin E(2) (PGE(2)) increased approximately 6-fold, compared with the normal esophageal mucosa. The higher expression of COX-1, the up-regulated COX-2 expression and the increased levels of PGE(2) synthesis were all significantly decreased by administering resveratrol. Our study suggests that resveratrol suppressed NMBA-induced rat esophageal tumorigenesis by targeting COXs and PGE(2), and therefore may be a promising natural anti-carcinogenesis agent for the prevention and treatment of human esophageal cancer.
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, 54-Shogoin, Kawahra-cho, Sakyoku, Kyoto 606-8507, Japan.
Zhi Gang
ZG
Li
Tao
T
Hong
Yutaka
Y
Shimada
Izumi
I
Komoto
Atsushi
A
Kawabe
Yongzeng
Y
Ding
Junichi
J
Kaganoi
Yosuke
Y
Hashimoto
Masayuki
M
Imamura
D000818:Animals; D015197:Carcinogenicity Tests; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004128:Dimethylnitrosamine / Q000031:analogs & derivatives*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*; D014158:Transcription, Genetic / Q000187:drug effects
D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D013267:Stilbenes; C014707:nitrosobenzylmethylamine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone; D004128:Dimethylnitrosamine; D000077185:Resveratrol