title: Identification of avarol derivatives as potential antipsoriatic drugs using an in vitro model for keratinocyte growth and differentiation.
abstract: Avarol, a marine sesquiterpenoid hydroquinone, and 14 avarol derivatives have shown interesting anti-inflammatory properties in previous studies. In this study, avarol and derivatives were evaluated in high-throughput keratinocyte culture models using cytokeratin 10 and SKALP/Elafin expression as markers for respectively normal and psoriatic differentiation. Avarol and five of its derivatives (5, 10, 13, 14 and 15) were selected for further study. Only 10, 13, 14 and 15 were able to inhibit keratinocyte cell growth. Changes in expression levels of 22 genes were assessed by quantitative real time PCR (qPCR). From these genes, TNFalpha mRNA levels showed the strongest changes. For compound 13, 15 and dithranol (used as a model antipsoriatic drug), a dose-dependent downregulation of TNFalpha mRNA was found. The changes in TNFalpha mRNA were confirmed at the protein level for compound 13. Additionally, this compound was able to reduce also IL-8 and COX-2 mRNA levels and this effect was correlated with a reduction in COX-2 protein expression. The mechanism of action of this compound involves at least the inhibition of NF-kappaB-DNA binding activity. In conclusion, our high-throughput screening models in combination with quantitative assessment of changes in gene expression profiles identified the avarol derivative 13, a benzylamine derivative of avarol at the 4' position of benzoquinone ring, as an interesting anti-psoriatic drug candidate that inhibits keratinocyte cell growth and TNFalpha and COX-2 expression.
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, Av., Vicente Andrés Estellés s/n, 46100, Burjasot, Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Amigó
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
authors.forename: Diana
authors.initials: D
authors.lastname: Olthuis
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Rosa
authors.forename: Miguel
authors.initials: M
authors.lastname: Payá
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Terencio
authors.forename: Evert
authors.initials: E
authors.lastname: Lamme
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D047088:Dysidea / Q000737:chemistry; D053492:Elafin / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007633:Keratins / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D053492:Elafin; D016209:Interleukin-8; D008565:Membrane Proteins; C506806:PI3 protein, human; D012333:RNA, Messenger; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D007633:Keratins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C023663:avarol