Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice

Citation
A. Murakami et al., Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice, CANCER RES, 60(18), 2000, pp. 5059-5066
Citations number
56
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
60
Issue
18
Year of publication
2000
Pages
5059 - 5066
Database
ISI
SICI code
0008-5472(20000915)60:18<5059:IEOCNO>2.0.ZU;2-P
Abstract
The intake of citrus fruits has been suggested as a way to prevent the deve lopment of some types of human cancer. Nitric oxide (NO) is closely associa ted with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Cia rcs unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O-2(-)) genera tion was induced by a combination of lipopolysaccharide and IFN-gamma in mo use 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 We stern blotting, The in vivo anti-inflammatory and antitumor promoting activ ities were evaluated by topical TPA application to ICR mouse skin with meas urement of edema formation, epidermal thickness, leukocyte infiltration, hy drogen peroxide production, and the rate of proliferating cell nuclear anti gen-stained cells. As a result, nobiletin, a polymethoxyflavonoid, was iden tified as an inhibitor of both NO and O-2(-) generation, Nobiletin signific antly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second st age activation (oxidative insult by leukocytes)] by decreasing the inflamma tory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E-2 release. Nobiletin inh ibited dimethylbenz[a]anthracene (0.19 mu mol)/TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumo rs 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.