Abstract
We previously reported that 6‐shogaol strongly suppressed lipopolysaccharide‐induced overexpression of inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) in murine macrophages. In this study, we further compared curcumin, 6‐gingerol, and 6‐shogaol's molecular mechanism of action and their anti‐tumor properties. We demonstrate that topical application of 6‐shogaol more effectively inhibited 12‐O‐tetradecanoylphorbol 13‐acetate (TPA)‐stimulated transcription of iNOS and COX‐2 mRNA expression in mouse skin than curcumin and 6‐gingerol. Pretreatment with 6‐shogaol has resulted in the reduction of TPA‐induced nuclear translocation of the nuclear factor‐κB subunits. 6‐Shogaol also reduced TPA‐induced phosphorylation of IκBα and p65, and caused subsequent degradation of IκBα. Moreover, 6‐shogaol markedly suppressed TPA‐induced activation of extracellular signal‐regulate kinase1/2, p38 mitogen‐activated protein kinase, JNK1/2, and phosphatidylinositol 3‐kinase/Akt, which are upstream of nuclear factor‐κB and AP‐1. Furthermore, 6‐shogaol significantly inhibited 7,12‐dimethylbenz[a]anthracene/TPA‐induced skin tumor formation measured by the tumor multiplicity of papillomas at 20 wk. Presented data reveal for the first time that 6‐shogaol is an effective anti‐tumor agent that functions by down‐regulating inflammatory iNOS and COX‐2 gene expression in mouse skin. It is suggested that 6‐shogaol is a novel functional agent capable of preventing inflammation‐associated tumorigenesis.