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

Abstract
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.
AuthorsMasahito Shimizu, Takahiro Kochi, Yohei Shirakami, Salvatore Genovese, Francesco Epifano, Serena Fiorito, Takayuki Mori, Takuji Tanaka, Hisataka Moriwaki
JournalInternational journal of cancer (Int J Cancer) Vol. 135 Issue 4 Pg. 774-84 (Aug 15 2014) ISSN: 1097-0215 [Electronic] United States
PMID24474144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 UICC.
Chemical References
  • 4'-geranyloxyferulic acid
  • 4'-geranyloxyferulic acid-N(omega)-nitroarginine methyl ester
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Coumaric Acids
  • Cytokines
  • Pdcd4 protein, mouse
  • RNA-Binding Proteins
  • Nitroarginine
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • NG-Nitroarginine Methyl Ester
Topics
  • Adenocarcinoma (drug therapy)
  • Adenoma (drug therapy)
  • Animals
  • Antineoplastic Agents (chemistry, pharmacology)
  • Apoptosis
  • Apoptosis Regulatory Proteins (metabolism)
  • Carcinogenesis (drug effects)
  • Cell Proliferation
  • Colorectal Neoplasms (drug therapy)
  • Coumaric Acids (chemistry, pharmacology)
  • Cyclooxygenase 2 (metabolism)
  • Cytokines (metabolism)
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Inflammation
  • Intestinal Mucosa (drug effects)
  • Male
  • Mice
  • Mice, Inbred ICR
  • NG-Nitroarginine Methyl Ester (chemistry, pharmacology)
  • Nitric Oxide Synthase Type II (metabolism)
  • Nitroarginine (analogs & derivatives, chemistry, pharmacology)
  • RNA-Binding Proteins (metabolism)

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