Anti-inflammatory and antitumor promotional effects of a novel urinary metabolite, 3',4'-didemethylnobiletin, derived from nobiletin.
We reported previously that 3',4'-didemethylnobiletin (DDMN) is the major metabolite of nobiletin in mouse urine. In this study, we examined DDMN's molecular mechanism of action and its anti-inflammatory and antitumor properties. We demonstrated that topical application of DDMN effectively inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated transcription of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and ornithine decarboxylase (ODC) messenger RNA and protein expression in mouse skin. Pretreatment with DDMN has resulted in the reduction of TPA-induced nuclear translocation of the nuclear factor-kappa B (NF-kappaB) subunit. DDMN also reduced DNA binding by blocking phosphorylation of inhibitor kappaB (IkappaB) alpha and p65 and caused subsequent degradation of IkappaBalpha. DDMN inhibited TPA-induced phosphorylation and nuclear translocation of the signal transducer and activator of transcription 3. Moreover, DDMN suppressed TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-kappaB and activator protien-1. We also found that DDMN significantly inhibited TPA-induced mouse skin inflammation by decreasing inflammatory parameters. Furthermore, DDMN significantly inhibited 7,12-dimethylbenz[a]anthracene/TPA-induced skin tumor formation measured by the tumor multiplicity of papillomas at 20 weeks. Presented data for the first time reveal that DDMN is an effective antitumor agent that functions by downregulating inflammatory iNOS, COX-2 and ODC gene expression in mouse skin. It is suggested that DDMN is a novel functional agent capable of preventing inflammation-associated tumorigenesis.
Lai
Ching-Shu
CS
Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan.
Li
Shiming
S
Chai
Chee-Yin
CY
Lo
Chih-Yu
CY
Dushenkov
Slavik
S
Ho
Chi-Tang
CT
Pan
Min-Hsiung
MH
Wang
Ying-Jan
YJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001551:Benz(a)Anthracenes / Q000633:toxicity; D015153:Blotting, Western; D015197:Carcinogenicity Tests; D051546:Cyclooxygenase 2 / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D047309:Flavones / Q000378:metabolism / Q000494:pharmacology* / Q000652:urine; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects; D009955:Ornithine Decarboxylase / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D018808:Transcription Factor AP-1 / Q000187:drug effects
C534647:3',4'-didemethylnobiletin; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D001551:Benz(a)Anthracenes; D047309:Flavones; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D018808:Transcription Factor AP-1; C046810:7,12-dihydroxymethylbenz(a)anthracene; C008661:nobiletin; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D009955:Ornithine Decarboxylase