A newly synthesized compound, 4'-geranyloxyferulic acid-N(omega)-nitro-L-arginine methyl ester suppresses inflammation-associated colorectal carcinogenesis in male mice.
We previously reported the cancer chemopreventive activity of 4'-geranyloxyferulic acid (GOFA, Miyamoto et al., Nutr Cancer 2008; 60:675-84) and a β-cyclodextrin inclusion compound of GOFA (Tanaka et al., Int J Cancer 2010; 126:830-40) in colitis-related colorectal carcinogenesis. In our study, the chemopreventive effects of a newly synthesized GOFA-containing compound, GOFA-N(omega)-nitro-L-arginine methyl ester (L-NAME), which inhibits inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX) enzymes, were investigated using a colitis-associated mouse colorectal carcinogenesis model with azoxymethane (AOM) and dextran sodium sulfate (DSS). The dietary administration of GOFA-L-NAME after the AOM and DSS treatments significantly reduced the multiplicity of adenocarcinomas (inhibition rates: 100 ppm, 84%, p < 0.001; 500 ppm, 94%, p < 0.001) compared with the AOM + DSS group. Dietary GOFA-L-NAME significantly decreased the proliferation (p < 0.001) and increased the apoptosis (p < 0.001) of colonic adenocarcinoma cells. A subsequent short-term experiment revealed that dietary GOFA-L-NAME decreased the mRNA expression of inflammatory enzymes, such as iNOS and COX-2, and proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and macrophage inflammatory protein (MIP)-2 in the colonic mucosa of mice that received 1.5% DSS in their drinking water for 7 days. Our findings indicate that GOFA-L-NAME is able to inhibit colitis-associated colon carcinogenesis by modulating inflammation, proliferation, apoptosis and the expression of proinflammatory cytokines in mice.
Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.
Masahito
M
Shimizu
Takahiro
T
Kochi
Yohei
Y
Shirakami
Salvatore
S
Genovese
Francesco
F
Epifano
Serena
S
Fiorito
Takayuki
T
Mori
Takuji
T
Tanaka
Hisataka
H
Moriwaki
D000230:Adenocarcinoma / Q000188:drug therapy; D000236:Adenoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D007249:Inflammation; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019331:NG-Nitroarginine Methyl Ester / Q000737:chemistry / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019335:Nitroarginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism
C552732:4'-geranyloxyferulic acid; C000590392:4'-geranyloxyferulic acid-N(omega)-nitroarginine methyl ester; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D003373:Coumaric Acids; D016207:Cytokines; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D019335:Nitroarginine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D019331:NG-Nitroarginine Methyl Ester
GOFA-L-NAME; MIP-2; PDCD4; azoxymethane; chemoprevention; colitis; colorectal cancer; cytokines; dextran sodium sulfate; mice