title: Hexahydro-β-acids potently inhibit 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumor promotion in mice.
abstract: 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-β-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 μg 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-κB. Furthermore, application of HBA (1 and 10 μg) 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).
authors.affiliation: Department of Nuclear Medicine, Taipei Medical University Hospital , Taipei 110, Taiwan.
authors.forename: Chung-Huei
authors.initials: CH
authors.lastname: Hsu
authors.forename: Yuan-Soon
authors.initials: YS
authors.lastname: Ho
authors.forename: Ching-Shu
authors.initials: CS
authors.lastname: Lai
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Hsieh
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Chen
authors.forename: Edwin
authors.initials: E
authors.lastname: Lin
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: Min-Hsiung
authors.initials: MH
authors.lastname: Pan
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy* / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D027582:Humulus / Q000737:chemistry; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate