Carcinogenesis Advance Access originally published online on September 26, 2008
Carcinogenesis 2008 29(12):2415-2424; doi:10.1093/carcin/bgn222
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Anti-inflammatory and antitumor promotional effects of a novel urinary metabolite, 3',4'-didemethylnobiletin, derived from nobiletin
1 Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan 704, Taiwan
2 Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA
3 Department of Pathology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
4 Department of Food Science, National Chiayi University, Chiayi City 60004, Taiwan
5 Biotech Center, Rutgers University, New Brunswick, NJ 08901, USA
6 Graduate Institute of Food Science and Technology, National Taiwan University, Taipei 100, Taiwan
7 Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung 811, Taiwan
* To whom correspondence should be addressed. Tel: +886 7 361 7141; Fax: +886 7 361 1261; Email: mhpan{at}mail.nkmu.edu.tw
Correspondence may also be addressed to Ying-Jan Wang. Tel: +886 6 235 3535 ext. 5804; Fax: +886 6 275 2484; Email: yjwang{at}mail.ncku.edu.tw
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-
B) subunit. DDMN also reduced DNA binding by blocking phosphorylation of inhibitor B (IB) 
and p65 and caused subsequent degradation of IB. 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-B 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.
Abbreviations: AP-1, activator protien-1; COX, cyclooxygenase; DDMN, 3',4'-didemethylnobiletin; DMBA, 7,12-dimethylbenz[a]anthracene; EDTA, ethylenediaminetetraacetic acid; ERK, extracellular signal-regulated kinase; IB, inhibitor B; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; MMP-9, matrix metalloproteinase-9; NF-B, nuclear factor-kappa B; NP-40, Nonidet P-40; ODC, ornithine decarboxylase; PCNA, proliferating cell nuclear antigen; PCR, polymerase chain reaction; PDTC, pyrrolidine dithiocarbamate; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; STAT, signal transducer and activator of transcription; TPA, 12-O-tetradecanoylphorbol-13-acetate; VEGF, vascular endothelial growth factor
Received March 23, 2008; revised September 16, 2008; accepted September 18, 2008.