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
Journal
Carcinogenesis
Journal Volume
28
Journal Issue
12
Pages
2581-2588
Date Issued
2007
Author(s)
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-κB (NF-κB) subunit and DNA binding by blocking phosphorylation of inhibitor κB (IκB) α and p65 and subsequent degradation of IκBα. 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-κB. 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. ? The Author 2007. Published by Oxford University Press. All rights reserved.
SDGs
Other Subjects
5 hydroxy 3,6,7,8,3',4' hexamethoxyflavone; 7,12 dimethylbenz[a]anthracene; citrus fruit extract; cyclooxygenase 2; DNA; flavone derivative; I kappa B alpha; immunoglobulin enhancer binding protein; inducible nitric oxide synthase; messenger RNA; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase p38; phorbol 13 acetate 12 myristate; phosphatidylinositol 3 kinase; protein kinase B; serine; STAT3 protein; synaptotagmin I; tyrosine; unclassified drug; animal cell; animal experiment; animal model; animal tissue; antiinflammatory activity; article; cancer inhibition; cell nucleus; citrus fruit; controlled study; down regulation; drug DNA binding; drug efficacy; female; gene expression regulation; intracellular transport; mouse; nonhuman; nucleotide sequence; papilloma; priority journal; protein degradation; protein expression; protein phosphorylation; skin carcinogenesis; skin inflammation; skin tumor; sweet orange; transcription regulation; tumor promotion; 1-Phosphatidylinositol 3-Kinase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Citrus; Cyclooxygenase 2; Dermatitis; Extracellular Signal-Regulated MAP Kinases; Female; Flavones; I-kappa B Kinase; Mice; Mice, Inbred ICR; NF-kappa B; Nitric Oxide Synthase Type II; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Skin Neoplasms; STAT3 Transcription Factor; Tetradecanoylphorbol Acetate
Type
journal article