Carcinogenesis Advance Access published online on October 24, 2007
Carcinogenesis, doi:10.1093/carcin/bgm231
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Inhibitory effect of citrus 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone on 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumor promotion in mice
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 08901-8520, USA
3 Department of Pathology, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Department of Food Science, National Chiayi University, Chiayi, Taiwan
5 Graduate Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan
6 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
5-Hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-OH-HxMF), a polymethoxyflavone, is found exclusively in the Citrus genus, particularly in the peels of sweet orange. Herein, we report the first investigation of the inhibitory effects of 5-OH-HxMF on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in mouse skin. We found that the topical application of 5-OH-HxMF can effectively inhibit the transcriptional activation of iNOS and COX-2 mRNA and protein in mouse skin stimulated by TPA. Pretreatment with 5-OH-HxMF resulted in the reduction of TPA-induced nuclear translocation of nuclear factor-
B (NFB) subunit and DNA binding by blocking phosphorylation of IB
and p65 and subsequent degradation of IB. In addition, 5-OH-HxMF can inhibit TPA-induced phosphorylation and nuclear translocation of the signal transducer and activator of transcription-3 (STAT3). Moreover, 5-OH-HxMF can suppress TPA-induced activation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt, which are upstream of NFB. We also found that 5-OH-HxMF significantly inhibited TPA-induced mouse skin inflammation by decreasing inflammatory parameters. Furthermore, 5-OH-HxMF significantly inhibited 7,12-dimethylbene[a]anthracene (DMBA)/TPA-induced skin tumor formation by reducing the tumor incidence and tumor multiplicity of papillomas at 20 weeks. Therefore, all these results revealed for the first time that 5-OH-HxMF is an effective antitumor agent and its inhibitory effect is through the down-regulation of inflammatory iNOS and COX-2 gene expression in mouse skin, suggesting that 5-OH-HxMF is a novel functional agent capable of preventing inflammation-associated tumorigenesis.
Received July 29, 2007; revised October 10, 2007; accepted October 15, 2007.
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