A novel prodrug of 4'-geranyloxy-ferulic acid suppresses colitis-related colon carcinogenesis in mice.
The inhibitory effects of a novel prodrug, 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline (GAP), of the secondary metabolite 4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid (4'-geranyloxy-ferulic acid), on colon carcinogenesis was investigated using an azoxymetahen (AOM)/dextran sodium sulfate (DSS) model. GAP was synthetically derived from ferulic acid. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) were promoted by 1% (wt/vol) DSS in drinking water for 7 days. They were then given modified AIN-76A diet containing 0.01% or 0.05% GAP for 17 wk. At Week 20, the development of colonic adenocarcinoma was significantly inhibited by GAP feeding at dose levels of 0.01% [60% incidence (P = 0.0158) with a multiplicity of and 1.13 +/- 1.13 (P < 0.05)] and 0.05% [53% incidence (P = 0.0057) with a multiplicity of 0.08 +/- 1.08 (P < 0.01)], when compared to the AOM/DSS group (95% incidence with a multiplicity of 3.10 +/- 3.06). Dietary GAP modulated the mitotic and apoptotic indexes in the crypt cells and lowered 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells in the colonic mucosa. Urinary level of 8-OHdG was lowered by GAP feeding. Additionally, dietary GAP elevated the immunoreactivity of an inducible form of heme oxygenase 1 in the colonic mucosa. Our results indicate that GAP is able to inhibit colitis-related colon carcinogenesis by modulating proliferation and oxidative stress in mice.
Miyamoto
Shingo
S
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
Epifano
Francesco
F
Curini
Massimo
M
Genovese
Salvatore
S
Kim
Mihye
M
Ishigamori-Suzuki
Rikako
R
Yasui
Yumiko
Y
Sugie
Shigeyuki
S
Tanaka
Takuji
T
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000230:Adenocarcinoma / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D001397:Azoxymethane; D002273:Carcinogens; D018890:Chemoprevention / Q000379:methods; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology / Q000517:prevention & control*; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D016264:Dextran Sulfate; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018384:Oxidative Stress / Q000187:drug effects; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*
C535007:3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D003373:Coumaric Acids; D004151:Dipeptides; D011355:Prodrugs; D000080242:8-Hydroxy-2'-Deoxyguanosine; D016264:Dextran Sulfate; C004999:ferulic acid; D006419:Heme Oxygenase (Decyclizing); D003849:Deoxyguanosine; D001397:Azoxymethane