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A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia
This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes...
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| Published in: | The pharmacogenomics journal 2018-01, Vol.18 (1), p.56-63 |
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| container_end_page | 63 |
| container_issue | 1 |
| container_start_page | 56 |
| container_title | The pharmacogenomics journal |
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| creator | Mannarino, L Paracchini, L Craparotta, I Romano, M Marchini, S Gatta, R Erba, E Clivio, L Romualdi, C D’Incalci, M Beltrame, L Pattini, L |
| description | This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes inferred for specific transcription factors, among which
MAFB
was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells. Using the Connectivity Map, similarity among transcriptional signatures elicited by treatment with different compounds was investigated, showing a high degree of similarity between transcriptional signatures of trabectedin and those of the topoisomerase I inhibitor, irinotecan, and an anti-dopaminergic antagonist, thioridazine. The study highlights the potential importance of systems biology approaches to generate new hypotheses that are experimentally testable to define the specificity of the mechanism of action of drugs. |
| doi_str_mv | 10.1038/tpj.2016.76 |
| format | article |
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MAFB
was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells. Using the Connectivity Map, similarity among transcriptional signatures elicited by treatment with different compounds was investigated, showing a high degree of similarity between transcriptional signatures of trabectedin and those of the topoisomerase I inhibitor, irinotecan, and an anti-dopaminergic antagonist, thioridazine. The study highlights the potential importance of systems biology approaches to generate new hypotheses that are experimentally testable to define the specificity of the mechanism of action of drugs.</description><identifier>ISSN: 1470-269X</identifier><identifier>EISSN: 1473-1150</identifier><identifier>DOI: 10.1038/tpj.2016.76</identifier><identifier>PMID: 27958379</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/31 ; 38/39 ; 38/61 ; 38/77 ; 631/114/2114 ; 631/67/69 ; Antineoplastic Agents, Alkylating - therapeutic use ; Biology ; Biomedical and Life Sciences ; Biomedicine ; Cell Line, Tumor ; Complications and side effects ; DNA topoisomerase ; Dopamine ; Dopamine receptors ; Dosage and administration ; Drug therapy ; Gene Expression ; Gene Expression Profiling - methods ; Gene Regulatory Networks - drug effects ; Genetic aspects ; Health aspects ; Human Genetics ; Humans ; Investigations ; Irinotecan ; Leukemia ; Leukemia, Myeloid - drug therapy ; Mode of action ; Myelomonocytic leukemia ; Oncology ; Original ; original-article ; Pharmacotherapy ; Psychopharmacology ; Studies ; Systems Biology - methods ; Thioridazine ; Trabectedin ; Trabectedin - pharmacology ; Transcription factors ; Transcription, Genetic - drug effects</subject><ispartof>The pharmacogenomics journal, 2018-01, Vol.18 (1), p.56-63</ispartof><rights>The Author(s) 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 2018</rights><rights>Copyright © 2018 The Author(s) 2018 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-54cfda298f2008c155b142d800399239c36f8bfdf92d7faae6d8bd15eccf613</citedby><cites>FETCH-LOGICAL-c513t-54cfda298f2008c155b142d800399239c36f8bfdf92d7faae6d8bd15eccf613</cites><orcidid>0000-0003-2237-0961</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27958379$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mannarino, L</creatorcontrib><creatorcontrib>Paracchini, L</creatorcontrib><creatorcontrib>Craparotta, I</creatorcontrib><creatorcontrib>Romano, M</creatorcontrib><creatorcontrib>Marchini, S</creatorcontrib><creatorcontrib>Gatta, R</creatorcontrib><creatorcontrib>Erba, E</creatorcontrib><creatorcontrib>Clivio, L</creatorcontrib><creatorcontrib>Romualdi, C</creatorcontrib><creatorcontrib>D’Incalci, M</creatorcontrib><creatorcontrib>Beltrame, L</creatorcontrib><creatorcontrib>Pattini, L</creatorcontrib><title>A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia</title><title>The pharmacogenomics journal</title><addtitle>Pharmacogenomics J</addtitle><addtitle>Pharmacogenomics J</addtitle><description>This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes inferred for specific transcription factors, among which
MAFB
was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells. Using the Connectivity Map, similarity among transcriptional signatures elicited by treatment with different compounds was investigated, showing a high degree of similarity between transcriptional signatures of trabectedin and those of the topoisomerase I inhibitor, irinotecan, and an anti-dopaminergic antagonist, thioridazine. The study highlights the potential importance of systems biology approaches to generate new hypotheses that are experimentally testable to define the specificity of the mechanism of action of drugs.</description><subject>13/31</subject><subject>38/39</subject><subject>38/61</subject><subject>38/77</subject><subject>631/114/2114</subject><subject>631/67/69</subject><subject>Antineoplastic Agents, Alkylating - therapeutic use</subject><subject>Biology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell Line, Tumor</subject><subject>Complications and side effects</subject><subject>DNA topoisomerase</subject><subject>Dopamine</subject><subject>Dopamine receptors</subject><subject>Dosage and administration</subject><subject>Drug therapy</subject><subject>Gene Expression</subject><subject>Gene Expression Profiling - methods</subject><subject>Gene Regulatory Networks - drug effects</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Investigations</subject><subject>Irinotecan</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid - drug therapy</subject><subject>Mode of action</subject><subject>Myelomonocytic leukemia</subject><subject>Oncology</subject><subject>Original</subject><subject>original-article</subject><subject>Pharmacotherapy</subject><subject>Psychopharmacology</subject><subject>Studies</subject><subject>Systems Biology - methods</subject><subject>Thioridazine</subject><subject>Trabectedin</subject><subject>Trabectedin - pharmacology</subject><subject>Transcription factors</subject><subject>Transcription, Genetic - drug effects</subject><issn>1470-269X</issn><issn>1473-1150</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNptks-P1CAUxxujcdfVk3dD4sVEOwIdKFw2mWz8lWziQQ_eCKWPDmMLtdBJ-t9LnXXXNRsOEN7nfXnv8S2KlwRvCK7E-zQeNhQTvqn5o-KcbOuqJIThx3_OuKRc_jgrnsV4wBkitXhanNFaMlHV8rw47lBcYoIhosaFPnQL0uM4BW32KAXk_BFicp1OgNIe0ABmr72LAwoWaZNc8OspTboBk6B1PqcgjYbQQr9GhgX6MAQfzJKcQT3MP2Fw-nnxxOo-woub_aL49vHD96vP5fXXT1-udtelYaRKJdsa22oqhaUYC0MYa8iWtgLjSkpaSVNxKxrbWknb2moNvBVNSxgYYzmpLorLk-o4NwO0BnwutFfj5AY9LSpop-5HvNurLhwVE6SuJMsCb24EpvBrzpNQg4sG-l57CHNURDDKueASZ_T1f-ghzJPPzalce_4fsuX8jup0D8p5G_K7ZhVVO0ZrhumJ2jxA5dXm2Zngwbp8fy_h7SnBTCHGCextjwSr1SQqm0StJlH1Sr_6dyy37F9XZODdCYg55DuY7np5SO83-e3INw</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Mannarino, L</creator><creator>Paracchini, L</creator><creator>Craparotta, I</creator><creator>Romano, M</creator><creator>Marchini, S</creator><creator>Gatta, R</creator><creator>Erba, E</creator><creator>Clivio, L</creator><creator>Romualdi, C</creator><creator>D’Incalci, M</creator><creator>Beltrame, L</creator><creator>Pattini, L</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2237-0961</orcidid></search><sort><creationdate>20180101</creationdate><title>A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia</title><author>Mannarino, L ; Paracchini, L ; Craparotta, I ; Romano, M ; Marchini, S ; Gatta, R ; Erba, E ; Clivio, L ; Romualdi, C ; D’Incalci, M ; Beltrame, L ; Pattini, L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-54cfda298f2008c155b142d800399239c36f8bfdf92d7faae6d8bd15eccf613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>13/31</topic><topic>38/39</topic><topic>38/61</topic><topic>38/77</topic><topic>631/114/2114</topic><topic>631/67/69</topic><topic>Antineoplastic Agents, Alkylating - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The pharmacogenomics journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mannarino, L</au><au>Paracchini, L</au><au>Craparotta, I</au><au>Romano, M</au><au>Marchini, S</au><au>Gatta, R</au><au>Erba, E</au><au>Clivio, L</au><au>Romualdi, C</au><au>D’Incalci, M</au><au>Beltrame, L</au><au>Pattini, L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia</atitle><jtitle>The pharmacogenomics journal</jtitle><stitle>Pharmacogenomics J</stitle><addtitle>Pharmacogenomics J</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>18</volume><issue>1</issue><spage>56</spage><epage>63</epage><pages>56-63</pages><issn>1470-269X</issn><eissn>1473-1150</eissn><abstract>This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes inferred for specific transcription factors, among which
MAFB
was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells. Using the Connectivity Map, similarity among transcriptional signatures elicited by treatment with different compounds was investigated, showing a high degree of similarity between transcriptional signatures of trabectedin and those of the topoisomerase I inhibitor, irinotecan, and an anti-dopaminergic antagonist, thioridazine. The study highlights the potential importance of systems biology approaches to generate new hypotheses that are experimentally testable to define the specificity of the mechanism of action of drugs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27958379</pmid><doi>10.1038/tpj.2016.76</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-2237-0961</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/31 38/39 38/61 38/77 631/114/2114 631/67/69 Antineoplastic Agents, Alkylating - therapeutic use Biology Biomedical and Life Sciences Biomedicine Cell Line, Tumor Complications and side effects DNA topoisomerase Dopamine Dopamine receptors Dosage and administration Drug therapy Gene Expression Gene Expression Profiling - methods Gene Regulatory Networks - drug effects Genetic aspects Health aspects Human Genetics Humans Investigations Irinotecan Leukemia Leukemia, Myeloid - drug therapy Mode of action Myelomonocytic leukemia Oncology Original original-article Pharmacotherapy Psychopharmacology Studies Systems Biology - methods Thioridazine Trabectedin Trabectedin - pharmacology Transcription factors Transcription, Genetic - drug effects |
| title | A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia |
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