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.