Open AccessMetformin suppresses intestinal polyp growth in Apc Min/+ mice
Author(s) -
Tomimoto Ayako,
Endo Hiroki,
Sugiyama Michiko,
Fujisawa Toshio,
Hosono Kunihiro,
Takahashi Hirokazu,
Nakajima Noriko,
Nagashima Yoji,
Wada Koichiro,
Nakagama Hitoshi,
Nakajima Atsushi
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.00933.x
Subject(s) - metformin , ampk , medicine , endocrinology , cyclin d1 , cell growth , amp activated protein kinase , biguanide , apoptosis , biology , protein kinase a , cancer , diabetes mellitus , kinase , cell cycle , biochemistry
Metformin is a biguanide derivative that is widely used in the treatment of diabetes mellitus. One of the pharmacological targets of metformin is adenosine monophosphate‐activated protein kinase (AMPK). We investigated the effect of metformin on the suppression of intestinal polyp formation in Apc Min/+ mice. Administration of metformin (250 mg/kg) did not reduce the total number of intestinal polyp formations, but significantly reduced the number of intestinal polyp formations larger than 2 mm in diameter in Apc Min/+ mice. To examine the indirect effect of metformin, the index of insulin resistance and serum lipid levels in Apc Min/+ mice were assessed. These factors were not significantly attenuated by the treatment with metformin, indicating that the suppression of polyp growth is not due to the indirect drug action. The levels of tumor cell proliferation as determined by 5‐bromodeoxyuridine and proliferating cell nuclear antigen immunohistochemical staining, and apoptosis, via transferase deoxytidyl uridine end labeling staining, in the polyps of metformin‐treated mice were not significantly different in comparison to those of control mice. Gene expression of cyclin D1 and c‐myc in intestinal polyps were also not significantly different between those two groups. In contrast, metformin activated AMPK in the intestinal polyps, resulting in the inhibition of the activation of mammalian target of rapamycin, which play important roles in the protein synthesis machinery. Metformin suppressed the polyp growth in Apc Min/+ mice, suggesting that it may be a novel candidate as a chemopreventive agent for colorectal cancer. ( Cancer Sci 2008; 99: 2136–2141)