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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.

Abstract
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. Pre-treatment with 5-OH-HxMF resulted in the reduction of TPA-induced nuclear translocation of nuclear factor-kappaB (NF-kappaB) subunit and DNA binding by blocking phosphorylation of inhibitor kappaB (IkappaB) alpha and p65 and subsequent degradation of IkappaBalpha. In addition, 5-OH-HxMF can inhibit TPA-induced phosphorylation and nuclear translocation of the signal transducer and activator of transcription-3. Moreover, 5-OH-HxMF can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt, which are upstream of NF-kappaB. 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-dimethylbenz[a]anthracene/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.
AuthorsChing-Shu Lai, Shiming Li, Chee-Yin Chai, Chih-Yu Lo, Chi-Tang Ho, Ying-Jan Wang, Min-Hsiung Pan
JournalCarcinogenesis (Carcinogenesis) Vol. 28 Issue 12 Pg. 2581-8 (Dec 2007) ISSN: 1460-2180 [Electronic] England
PMID17962218 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents, Phytogenic
  • Flavones
  • NF-kappa B
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone
  • Nitric Oxide Synthase Type II
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • I-kappa B Kinase
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
  • Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
  • Citrus (chemistry)
  • Cyclooxygenase 2 (biosynthesis)
  • Dermatitis (drug therapy)
  • Extracellular Signal-Regulated MAP Kinases (metabolism)
  • Female
  • Flavones (pharmacology, therapeutic use)
  • I-kappa B Kinase (metabolism)
  • Mice
  • Mice, Inbred ICR
  • NF-kappa B (metabolism)
  • Nitric Oxide Synthase Type II (biosynthesis)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt (metabolism)
  • STAT3 Transcription Factor (metabolism)
  • Skin Neoplasms (chemically induced, prevention & control)
  • Tetradecanoylphorbol Acetate
  • p38 Mitogen-Activated Protein Kinases (metabolism)

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