Carcinogenesis Advance Access published online on September 26, 2008
Carcinogenesis, doi:10.1093/carcin/bgn222
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Anti-inflammatory and anti-tumor 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, New Jersey 08901, USA
3 Department of Pathology, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Department of Food Science, National Chiayi University, Chiayi City 60004, Taiwan
5 Biotech Center, Rutgers University, New Brunswick, New Jersey, 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
* Please send all correspondence to: Dr. Min-Hsiung Pan, Department of Seafood Science, National Kaohsiung Marine University, No. 142, Hai-Chuan Rd, Nan-Tzu, Kaohsiung, Taiwan. Tel. no. (886)-7-361-7141, Fax. no. (886)-7-361-1261, E-mail: mhpan{at}mail.nkmu.edu.tw and Dr. Ying-Jan Wang, Department of Environmental and Occupational Health, National Cheng Kung University Medical College, 138 Sheng-Li Road, Tainan 70428, Taiwan, Tel: 886-6-235-3535 ext. 5804, Fax: 886-6-2752484, E-mail: yjwang{at}mail.ncku.edu.tw
We previously reported 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 anti-tumor properties. We demonstrated that topical application of DDMN effectively inhibited O-tetradecanoylphorbol-13-acetate (TPA)-stimulated transcription nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and ornithine decarboxylase (ODC) mRNA and protein expression in mouse skin.
Pretreatment with DDMN has resulted in the reduction of TPA-induced nuclear translocation of the nuclear factor-
B (NFB) subunit. DDMN also reduced DNA binding by blocking phosphorylation of 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 (STAT3). Moreover, DDMN suppressed TPA-induced activation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and PKC which are upstream of NFB and AP-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 (DMBA)/TPA-induced skin tumor formation measured by the tumor multiplicity of papillomas at 20 weeks. Presented data for the first time reveals that DDMN is an effective anti-tumor agent that functions by down-regulating 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.
Received March 23, 2008; revised September 16, 2008; accepted September 18, 2008.