A newly synthesized compound, 4 %26apos;-geranyloxyferulic acid-N(omega)-nitro-L-arginine methyl ester suppresses inflammation-associated colorectal carcinogenesis in male mice

作者：Shimizu Masahito^*; Kochi Takahiro; Shirakami Yohei; Genovese Salvatore; Epifano Francesco; Fiorito Serena; Mori Takayuki; Tanaka Takuji; Moriwaki Hisataka

来源：International Journal of Cancer, 2014, 135(4): 774-784.

DOI：10.1002/ijc.28718

• GOFA-L-NAME
• chemoprevention
• PDCD4
• cytokines
• MIP-2
• colitis
• azoxymethane
• dextran sodium sulfate
• colorectal cancer
• mice

We previously reported the cancer chemopreventive activity of 4%26apos;-geranyloxyferulic acid (GOFA, Miyamoto et al., Nutr Cancer 2008; 60: 675-84) and a beta-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 %26lt; 0.001; 500 ppm, 94%, p %26lt; 0.001) compared with the AOM + DSS group. Dietary GOFA-L-NAME significantly decreased the proliferation (p %26lt; 0.001) and increased the apoptosis (p %26lt; 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-alpha, interleukin (IL) - 1 beta, 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.

• 出版日期2014-8-15