Identification of avarol derivatives as potential antipsoriatic drugs using an in vitro model for keratinocyte growth and differentiation
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 ma...
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| Veröffentlicht in: | Life sciences (1973) 2006-11, Vol.79 (25), p.2395-2404 |
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| creator | Amigó, María Schalkwijk, Joost Olthuis, Diana De Rosa, Salvatore Payá, Miguel Terencio, María Carmen Lamme, Evert |
| description | 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, TNFα mRNA levels showed the strongest changes. For compound
13,
15 and dithranol (used as a model antipsoriatic drug), a dose-dependent downregulation of TNFα mRNA was found. The changes in TNFα 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-κB-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 TNFα and COX-2 expression. |
| doi_str_mv | 10.1016/j.lfs.2006.08.003 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_68146971</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0024320506006254</els_id><sourcerecordid>68146971</sourcerecordid><originalsourceid>FETCH-LOGICAL-c351t-8bff03ccdb8a322dea30df8097d9ede44ffc99e7dd14f1de9d75ea000da8ddf83</originalsourceid><addsrcrecordid>eNp9kM9uEzEQhy0EomnhAXpBPnHb7Xi9f8UJVYVWqsQFzpbjGQenm3WwvVvlEXhrHBKpt55GmvnmN5qPsWsBpQDR3mzL0cayAmhL6EsA-YatRN8NBbRSvGUrgKouZAXNBbuMcQsATdPJ9-xCtEMnRTes2N8HpCk564xOzk_cW64XHfzIkYJbcnOhyHXke5-OoB65zmUffXB5aDiGeRP5HN20yRPuJr64FDzfeaSRWx_4E4VMTt4cEvFN8M_pdyaRo7OWwv_Q4-kP7J3VY6SP53rFfn27-3l7Xzz--P5w-_WxMLIRqejX1oI0Bte9llWFpCWg7WHocCCkurbWDAN1iKK2AmnAriGdX0fdYwblFft8yt0H_2emmNTORUPjqCfyc1RtL-qsR2RQnEATfIyBrNoHt9PhoASoo3-1Vdm_OvpX0KvsP-98OofP6x3hy8ZZeAa-nADKLy6OgorG0WQIXSCTFHr3Svw_JUGbyQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>68146971</pqid></control><display><type>article</type><title>Identification of avarol derivatives as potential antipsoriatic drugs using an in vitro model for keratinocyte growth and differentiation</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Amigó, María ; Schalkwijk, Joost ; Olthuis, Diana ; De Rosa, Salvatore ; Payá, Miguel ; Terencio, María Carmen ; Lamme, Evert</creator><creatorcontrib>Amigó, María ; Schalkwijk, Joost ; Olthuis, Diana ; De Rosa, Salvatore ; Payá, Miguel ; Terencio, María Carmen ; Lamme, Evert</creatorcontrib><description>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, TNFα mRNA levels showed the strongest changes. For compound
13,
15 and dithranol (used as a model antipsoriatic drug), a dose-dependent downregulation of TNFα mRNA was found. The changes in TNFα 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-κB-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 TNFα and COX-2 expression.</description><identifier>ISSN: 0024-3205</identifier><identifier>EISSN: 1879-0631</identifier><identifier>DOI: 10.1016/j.lfs.2006.08.003</identifier><identifier>PMID: 16973179</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Avarol ; Cell Differentiation - drug effects ; Cell Proliferation - drug effects ; Cells, Cultured ; COX-2 ; Cyclooxygenase 2 - genetics ; Cyclooxygenase 2 - metabolism ; Cytokeratin 10 ; Drug Evaluation, Preclinical ; Dysidea - chemistry ; Elafin - metabolism ; Enzyme-Linked Immunosorbent Assay ; Humans ; In Vitro Techniques ; Interleukin-8 - genetics ; Interleukin-8 - metabolism ; Keratinocytes ; Keratinocytes - drug effects ; Keratinocytes - metabolism ; Keratinocytes - pathology ; Keratins - metabolism ; Membrane Proteins - antagonists & inhibitors ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; NF-κB ; Psoriasis ; Psoriasis - drug therapy ; Psoriasis - metabolism ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Sesquiterpenes - chemistry ; Sesquiterpenes - pharmacology ; TNFα ; Tumor Necrosis Factor-alpha - pharmacology</subject><ispartof>Life sciences (1973), 2006-11, Vol.79 (25), p.2395-2404</ispartof><rights>2006 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c351t-8bff03ccdb8a322dea30df8097d9ede44ffc99e7dd14f1de9d75ea000da8ddf83</citedby><cites>FETCH-LOGICAL-c351t-8bff03ccdb8a322dea30df8097d9ede44ffc99e7dd14f1de9d75ea000da8ddf83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.lfs.2006.08.003$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16973179$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Amigó, María</creatorcontrib><creatorcontrib>Schalkwijk, Joost</creatorcontrib><creatorcontrib>Olthuis, Diana</creatorcontrib><creatorcontrib>De Rosa, Salvatore</creatorcontrib><creatorcontrib>Payá, Miguel</creatorcontrib><creatorcontrib>Terencio, María Carmen</creatorcontrib><creatorcontrib>Lamme, Evert</creatorcontrib><title>Identification of avarol derivatives as potential antipsoriatic drugs using an in vitro model for keratinocyte growth and differentiation</title><title>Life sciences (1973)</title><addtitle>Life Sci</addtitle><description>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, TNFα mRNA levels showed the strongest changes. For compound
13,
15 and dithranol (used as a model antipsoriatic drug), a dose-dependent downregulation of TNFα mRNA was found. The changes in TNFα 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-κB-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 TNFα and COX-2 expression.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Avarol</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>COX-2</subject><subject>Cyclooxygenase 2 - genetics</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Cytokeratin 10</subject><subject>Drug Evaluation, Preclinical</subject><subject>Dysidea - chemistry</subject><subject>Elafin - metabolism</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Interleukin-8 - genetics</subject><subject>Interleukin-8 - metabolism</subject><subject>Keratinocytes</subject><subject>Keratinocytes - drug effects</subject><subject>Keratinocytes - metabolism</subject><subject>Keratinocytes - pathology</subject><subject>Keratins - metabolism</subject><subject>Membrane Proteins - antagonists & inhibitors</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>NF-κB</subject><subject>Psoriasis</subject><subject>Psoriasis - drug therapy</subject><subject>Psoriasis - metabolism</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Sesquiterpenes - chemistry</subject><subject>Sesquiterpenes - pharmacology</subject><subject>TNFα</subject><subject>Tumor Necrosis Factor-alpha - pharmacology</subject><issn>0024-3205</issn><issn>1879-0631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM9uEzEQhy0EomnhAXpBPnHb7Xi9f8UJVYVWqsQFzpbjGQenm3WwvVvlEXhrHBKpt55GmvnmN5qPsWsBpQDR3mzL0cayAmhL6EsA-YatRN8NBbRSvGUrgKouZAXNBbuMcQsATdPJ9-xCtEMnRTes2N8HpCk564xOzk_cW64XHfzIkYJbcnOhyHXke5-OoB65zmUffXB5aDiGeRP5HN20yRPuJr64FDzfeaSRWx_4E4VMTt4cEvFN8M_pdyaRo7OWwv_Q4-kP7J3VY6SP53rFfn27-3l7Xzz--P5w-_WxMLIRqejX1oI0Bte9llWFpCWg7WHocCCkurbWDAN1iKK2AmnAriGdX0fdYwblFft8yt0H_2emmNTORUPjqCfyc1RtL-qsR2RQnEATfIyBrNoHt9PhoASoo3-1Vdm_OvpX0KvsP-98OofP6x3hy8ZZeAa-nADKLy6OgorG0WQIXSCTFHr3Svw_JUGbyQ</recordid><startdate>20061117</startdate><enddate>20061117</enddate><creator>Amigó, María</creator><creator>Schalkwijk, Joost</creator><creator>Olthuis, Diana</creator><creator>De Rosa, Salvatore</creator><creator>Payá, Miguel</creator><creator>Terencio, María Carmen</creator><creator>Lamme, Evert</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20061117</creationdate><title>Identification of avarol derivatives as potential antipsoriatic drugs using an in vitro model for keratinocyte growth and differentiation</title><author>Amigó, María ; Schalkwijk, Joost ; Olthuis, Diana ; De Rosa, Salvatore ; Payá, Miguel ; Terencio, María Carmen ; Lamme, Evert</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c351t-8bff03ccdb8a322dea30df8097d9ede44ffc99e7dd14f1de9d75ea000da8ddf83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Avarol</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>COX-2</topic><topic>Cyclooxygenase 2 - genetics</topic><topic>Cyclooxygenase 2 - metabolism</topic><topic>Cytokeratin 10</topic><topic>Drug Evaluation, Preclinical</topic><topic>Dysidea - chemistry</topic><topic>Elafin - metabolism</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Interleukin-8 - genetics</topic><topic>Interleukin-8 - metabolism</topic><topic>Keratinocytes</topic><topic>Keratinocytes - drug effects</topic><topic>Keratinocytes - metabolism</topic><topic>Keratinocytes - pathology</topic><topic>Keratins - metabolism</topic><topic>Membrane Proteins - antagonists & inhibitors</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>NF-κB</topic><topic>Psoriasis</topic><topic>Psoriasis - drug therapy</topic><topic>Psoriasis - metabolism</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Sesquiterpenes - chemistry</topic><topic>Sesquiterpenes - pharmacology</topic><topic>TNFα</topic><topic>Tumor Necrosis Factor-alpha - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Amigó, María</creatorcontrib><creatorcontrib>Schalkwijk, Joost</creatorcontrib><creatorcontrib>Olthuis, Diana</creatorcontrib><creatorcontrib>De Rosa, Salvatore</creatorcontrib><creatorcontrib>Payá, Miguel</creatorcontrib><creatorcontrib>Terencio, María Carmen</creatorcontrib><creatorcontrib>Lamme, Evert</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Life sciences (1973)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Amigó, María</au><au>Schalkwijk, Joost</au><au>Olthuis, Diana</au><au>De Rosa, Salvatore</au><au>Payá, Miguel</au><au>Terencio, María Carmen</au><au>Lamme, Evert</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of avarol derivatives as potential antipsoriatic drugs using an in vitro model for keratinocyte growth and differentiation</atitle><jtitle>Life sciences (1973)</jtitle><addtitle>Life Sci</addtitle><date>2006-11-17</date><risdate>2006</risdate><volume>79</volume><issue>25</issue><spage>2395</spage><epage>2404</epage><pages>2395-2404</pages><issn>0024-3205</issn><eissn>1879-0631</eissn><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, TNFα mRNA levels showed the strongest changes. For compound
13,
15 and dithranol (used as a model antipsoriatic drug), a dose-dependent downregulation of TNFα mRNA was found. The changes in TNFα 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-κB-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 TNFα and COX-2 expression.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>16973179</pmid><doi>10.1016/j.lfs.2006.08.003</doi><tpages>10</tpages></addata></record> |
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| subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Avarol Cell Differentiation - drug effects Cell Proliferation - drug effects Cells, Cultured COX-2 Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism Cytokeratin 10 Drug Evaluation, Preclinical Dysidea - chemistry Elafin - metabolism Enzyme-Linked Immunosorbent Assay Humans In Vitro Techniques Interleukin-8 - genetics Interleukin-8 - metabolism Keratinocytes Keratinocytes - drug effects Keratinocytes - metabolism Keratinocytes - pathology Keratins - metabolism Membrane Proteins - antagonists & inhibitors Membrane Proteins - genetics Membrane Proteins - metabolism NF-κB Psoriasis Psoriasis - drug therapy Psoriasis - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism Sesquiterpenes - chemistry Sesquiterpenes - pharmacology TNFα Tumor Necrosis Factor-alpha - pharmacology |
| title | Identification of avarol derivatives as potential antipsoriatic drugs using an in vitro model for keratinocyte growth and differentiation |
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