A novel geranylated derivative, ethyl 3-(4'-geranyloxy-3'-methoxyphenyl)-2-propenoate, synthesized from ferulic acid suppresses carcinogenesis and inducible nitric oxide synthase in rat tongue.
OBJECTIVE
We have previously observed the inhibitory effect of ferulic acid on rat tongue carcinogenesis. In this study, we investigated the modifying effects of a novel geranylated derivative, ethyl 3-(4'-geranyloxy-3'-methoxyphenyl)-2-propenoate (EGMP), synthesized from ferulic acid on tongue carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO).


METHODS
F344 male rats except those treated with EGMP alone and untreated rats were given 20 ppm 4-NQO in drinking water for 9 weeks to induce tongue neoplasms. Starting 1 week after the cessation of exposure to 4-NQO, the experimental groups given 4-NQO and a basal diet were fed the experimental diets containing EGMP (0.2% and 2%) for 20 weeks. The activities of glutathione S-transferase (GST) and quinone reductase (QR), the expression of proliferating cell nuclear antigen, polyamine content and ornithine decarboxylase activity in the tongue were examined for mechanistic analysis of modifying effects of EGMP on carcinogenesis. The expression of inducible nitric acid synthase (iNOS) was also assessed immunohistochemically.


RESULTS
At week 30, the incidence and multiplicity of tongue squamous cell carcinoma were significantly reduced by feeding of a 2% EGMP diet. EGMP feeding (2% in diet) elevated tongue GST activity and lowered QR activity in the tongue. Dietary EGMP decreased the expression of cell proliferation biomarker expression. Interestingly, EGMP feeding altered iNOS expression in the invasive parts of carcinoma.


CONCLUSIONS
These results suggest that EGMP, when given at the 2% dose level during the promotion phase, exerts a chemopreventive action against tongue tumorigenesis through modification of cell proliferation activity and/or detoxifying enzymatic activity.
Tanaka
Takuji
T
Department of Pathology, Kanazawa Medical University, Ishikawa, Japan. takutt@kanazawa-med.ac.jp
Kohno
Hiroyuki
H
Nomura
Eisaku
E
Taniguchi
Hisaji
H
Tsuno
Takuo
T
Tsuda
Hiroyuki
H
D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D003373:Coumaric Acids / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007150:Immunohistochemistry; D015994:Incidence; D008297:Male; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D015363:Quinolones; D051381:Rats; D011916:Rats, Inbred F344; D013729:Terpenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*
C120195:4-nitroquinolone-1-oxide; D014408:Biomarkers, Tumor; D002273:Carcinogens; D003373:Coumaric Acids; D016166:Free Radical Scavengers; D018809:Proliferating Cell Nuclear Antigen; D015363:Quinolones; D013729:Terpenes; C403134:ethyl-3-(4'-geranyloxy-3'-methoxyphenyl)-2-propenoate; D015112:4-Nitroquinoline-1-oxide; C004999:ferulic acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat