Anti-inflammatory and antitumor promotional effects of a novel urinary metabolite, 3′,4′-didemethylnobiletin, derived from nobiletin

Ching Shu Lai, Shiming Li, Chee Yin Chai, Chih Yu Lo, Slavik Dushenkov, Chi Tang Ho, Min Hsiung Pan, Ying Jan Wang

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

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-κB) subunit. DDMN also reduced DNA binding by blocking phosphorylation of inhibitor κB (IκB) α and p65 and caused subsequent degradation of IκBα. 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-κB 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.

Original languageEnglish (US)
Pages (from-to)2415-2424
Number of pages10
JournalCarcinogenesis
Volume29
Issue number12
DOIs
StatePublished - 2008

All Science Journal Classification (ASJC) codes

  • Cancer Research

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