Hexahydro-β-Acids Potently Inhibit 12-O-Tetradecanoylphorbol 13-Acetate-Induced Skin Inflammation and Tumor Promotion in Mice

We previously reported that hexahydro-beta-acids (HBAs), reduced derivatives of beta-acids (BA) from hop (Humulus lupulus L.), displayed more potent anti-inflammatory activity than BA in lipopolysaccharide-stimulated murine macrophages. In this study, we investigated the effects and underlying molecular mechanisms of hexahydro-beta-acids (HBAs) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated mouse skin inflammation and in the two-stage carcinogenesis model. Female ICR mice pretreated with HBA at 1 and 10 mu g significantly reduced ear edema, epidermal hyperplasia, and infiltration of inflammatory cells caused by TPA. Molecular analysis exhibited that HBA suppressed iNOS, COX-2, and ornithine decarboxylase (ODC) protein and gene expression through interfering with mitogen-activated protein kinases (MAPKs) and phosphatidylinositiol 3-kinase (PI3K)/Akt signaling as well as the activation of transcription factor NF-kappa B. Furthermore, application of HBA (1 and 10 mu g) prior to each TPA treatment (17.2 +/- 0.9 tumors/mouse) resulted in the significant reduction of tumor multiplicity (5.1 +/- 1.2, P < 0.01 and 2.3 +/- 1.2, P < 0.001, respectively) in 7,12-dimethyl-benzanthracene (DMBA)-initiated mouse skin. The tumor incidence was significantly lowered to 75% (P < 0.05) and 58.7% (P < 0.01) by HBA pretreatment, respectively, and significantly reduced the tumor weight (0.34 +/- 0.14 g, P < 0.01 and 0.09 +/- 0.10 g, P < 0.001, respectively) as compared to DMBA/TPA-induced tumors (0.76 +/- 0.04 g).