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Carcinogenesis |
Department of Biotechnological Science, Faculty of Biology-Oriented Science and Technology, Kinki University, Wakayama 649-6493 [A. M., T. K., K. K.]; Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502 [Y. N., K. T., H. O.]; First Department of Pathology, Kanazawa Medical University, Ishikawa 920-0293 [T. T.]; Research and Development Division, Wakayama Agricultural Processing Research Corporation, Nagagun, Wakayama 649-6112 [S. K., Y. T.]; Department of Citriculture, Fruit Tree Research Station, Shizuoka 424-0292 [K. O., M. Y.]; Department of Biochemistry, Kyoto Prefecture University of Medicine, Kyoto 602-0841 [H. T., H. N.]; Laboratory of Medicinal Plant Science, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392 [Y. M., Y. S.]; and Laboratory of Pharmacognosy, College of Pharmacy, Nihon University Chiba 274–8555 [S. K.], Japan
The intake of citrus fruits has been suggested as a way to prevent the
development of some types of human cancer. Nitric oxide (NO) is closely
associated with the processes of epithelial carcinogenesis. We
attempted a search for NO generation inhibitors in Citrus
unshiu. The active constituent was traced by an
activity-guiding separation. NO and superoxide
(O2-) generation was induced by a combination
of lipopolysaccharide and IFN-
in mouse macrophage RAW 264.7 cells,
and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in
differentiated human promyelocyte HL-60, respectively. Expression of
inducible NO synthase and cyclooxygenase 2 proteins were
detected by Western blotting. The in vivo
anti-inflammatory and antitumor promoting activities were evaluated by
topical TPA application to ICR mouse skin with measurement of edema
formation, epidermal thickness, leukocyte infiltration, hydrogen
peroxide production, and the rate of proliferating cell nuclear
antigen-stained cells. As a result, nobiletin, a polymethoxyflavonoid,
was identified as an inhibitor of both NO and
O2- generation. Nobiletin significantly
inhibited two distinct stages of skin inflammation induced by double
TPA application [first stage priming (leukocyte infiltration) and
second stage activation (oxidative insult by leukocytes)] by
decreasing the inflammatory parameters. It also suppressed the
expression of cyclooxygenase-2 and inducible NO synthase proteins and
prostaglandin E2 release. Nobiletin inhibited
dimethylbenz[a]anthracene (0.19 µmol)/TPA (1.6
nmol)-induced skin tumor formation at doses of 160 and 320 nmol by
reducing the number of tumors per mouse by 61.2%
(P < 0.001) and 75.7%
(P < 0.001), respectively. The present
study suggests that nobiletin is a functionally novel and possible
chemopreventive agent in inflammation-associated tumorigenesis.
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