(-)-Epigallocatechin gallate suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice.
Obesity and diabetes mellitus are risk factors for colon cancer. The activation of the insulin-like growth factor (IGF)/IGF-IR axis plays a critical role in this carcinogenesis. (-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, seems to have both antiobesity and antidiabetic effects. This study examined the effects of EGCG on the development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus. Male db/db mice were given four weekly s.c. injections of azoxymethane (15 mg/kg body weight) and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At sacrifice, drinking water with EGCG caused a significant decrease in the number of total aberrant crypt foci, large aberrant crypt foci, and beta-catenin accumulated crypts in these mice, all of which are premalignant lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3beta, beta-catenin, cyclooxygenase-2, and cyclin D1 proteins, and EGCG in drinking water caused a marked decrease in the expression of these proteins. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3 while conversely decreasing the serum levels of IGF-I, insulin, triglyceride, cholesterol, and leptin. EGCG overcomes the activation of the IGF/IGF-IR axis, thereby inhibiting the development of colonic premalignant lesions in an obesity-related colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. EGCG may be, therefore, useful in the chemoprevention or treatment of obesity-related colorectal cancer.
Shimizu
Masahito
M
Department of Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. shimim-gif@umin.ac.jp
Shirakami
Yohei
Y
Sakai
Hiroyasu
H
Adachi
Seiji
S
Hata
Kazuya
K
Hirose
Yoshinobu
Y
Tsurumi
Hisashi
H
Tanaka
Takuji
T
Moriwaki
Hisataka
H
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001397:Azoxymethane / Q000633:toxicity*; D002277:Carcinoma / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D007328:Insulin / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011230:Precancerous Conditions / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D016588:Anticarcinogenic Agents; D007328:Insulin; D020738:Leptin; D014280:Triglycerides; D002392:Catechin; D002784:Cholesterol; C045651:epigallocatechin gallate; D017526:Receptor, IGF Type 1; D001397:Azoxymethane