Suppression of azoxymethane-induced colonic preneoplastic lesions in rats by 1-methyltryptophan, an inhibitor of indoleamine 2,3-dioxygenase.
The escape of preneoplastic cells from the immune system, which is caused by immune tolerance, occurs during the development of several types of tumors. Indoleamine 2,3-dioxygenase (IDO) plays a critical role in the induction of immune tolerance. In the present study we investigated the effects of 1-methyltryptophan (1-MT), an IDO inhibitor, and (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, on the development of azoxymethane (AOM)-induced colonic preneoplastic lesions by focusing on the inhibition of IDO. To induce colonic premalignant lesions, male F344 rats were injected with AOM (20 mg/kg body weight, s.c.) once a week for 2 weeks. They also received 0.2% 1-MT or 0.1% EGCG in their drinking water for 4 weeks, starting 1 week before the first dose of AOM. Both 1-MT and EGCG significantly decreased the total number of aberrant crypt foci and β-catenin-accumulated crypts, which overexpressed IDO protein. Treatment with EGCG decreased IDO mRNA expression in both the colonic epithelium and stroma of rats induced by AOM. The AOM-induced increase in cyclooxygenase-2 mRNA expression in the colonic stroma was significantly decreased by EGCG. Furthermore, AOM-induced increases in IDO activity in the serum and stroma were significantly inhibited by 1-MT and EGCG. Inhibition of IDO activity by 1-MT and EGCG was also observed in cell-free assays. These findings suggest that upregulation of IDO activity is observed in the early stages of colon carcinogenesis and that the use of IDO inhibitors, such as 1-MT and EGCG, which suppress the occurrence of colonic preneoplastic lesions, could be a novel strategy for the chemoprevention of colon cancer.
First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
Kengo
K
Ogawa
Takeshi
T
Hara
Masahito
M
Shimizu
Soranobu
S
Ninomiya
Junji
J
Nagano
Hiroyasu
H
Sakai
Masato
M
Hoshi
Hiroyasu
H
Ito
Hisashi
H
Tsurumi
Kuniaki
K
Saito
Mitsuru
M
Seishima
Takuji
T
Tanaka
Hisataka
H
Moriwaki
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001397:Azoxymethane / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000139:chemically induced*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D001397:Azoxymethane; C525396:1-methyltryptophan