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CDA: Combinatorial Drug Discovery Using Transcriptional Response Modules

BACKGROUND: Anticancer therapies that target single signal transduction pathways often fail to prevent proliferation of cancer cells because of overlapping functions and cross-talk between different signaling pathways. Recent research has identified that balanced multi-component therapies might be m...

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Autores principales: Lee, Ji-Hyun, Kim, Dae Gyu, Bae, Tae Jeong, Rho, Kyoohyoung, Kim, Ji-Tae, Lee, Jong-Jun, Jang, Yeongjun, Kim, Byung Cheol, Park, Kyoung Mii, Kim, Sunghoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414439/
https://www.ncbi.nlm.nih.gov/pubmed/22905152
http://dx.doi.org/10.1371/journal.pone.0042573
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author Lee, Ji-Hyun
Kim, Dae Gyu
Bae, Tae Jeong
Rho, Kyoohyoung
Kim, Ji-Tae
Lee, Jong-Jun
Jang, Yeongjun
Kim, Byung Cheol
Park, Kyoung Mii
Kim, Sunghoon
author_facet Lee, Ji-Hyun
Kim, Dae Gyu
Bae, Tae Jeong
Rho, Kyoohyoung
Kim, Ji-Tae
Lee, Jong-Jun
Jang, Yeongjun
Kim, Byung Cheol
Park, Kyoung Mii
Kim, Sunghoon
author_sort Lee, Ji-Hyun
collection PubMed
description BACKGROUND: Anticancer therapies that target single signal transduction pathways often fail to prevent proliferation of cancer cells because of overlapping functions and cross-talk between different signaling pathways. Recent research has identified that balanced multi-component therapies might be more efficacious than highly specific single component therapies in certain cases. Ideally, synergistic combinations can provide 1) increased efficacy of the therapeutic effect 2) reduced toxicity as a result of decreased dosage providing equivalent or increased efficacy 3) the avoidance or delayed onset of drug resistance. Therefore, the interest in combinatorial drug discovery based on systems-oriented approaches has been increasing steadily in recent years. METHODOLOGY: Here we describe the development of Combinatorial Drug Assembler (CDA), a genomics and bioinformatics system, whereby using gene expression profiling, multiple signaling pathways are targeted for combinatorial drug discovery. CDA performs expression pattern matching of signaling pathway components to compare genes expressed in an input cell line (or patient sample data), with expression patterns in cell lines treated with different small molecules. Then it detects best pattern matching combinatorial drug pairs across the input gene set-related signaling pathways to detect where gene expression patterns overlap and those predicted drug pairs could likely be applied as combination therapy. We carried out in vitro validations on non-small cell lung cancer cells and triple-negative breast cancer (TNBC) cells. We found two combinatorial drug pairs that showed synergistic effect on lung cancer cells. Furthermore, we also observed that halofantrine and vinblastine were synergistic on TNBC cells. CONCLUSIONS: CDA provides a new way for rational drug combination. Together with phExplorer, CDA also provides functional insights into combinatorial drugs. CDA is freely available at http://cda.i-pharm.org.
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spelling pubmed-34144392012-08-19 CDA: Combinatorial Drug Discovery Using Transcriptional Response Modules Lee, Ji-Hyun Kim, Dae Gyu Bae, Tae Jeong Rho, Kyoohyoung Kim, Ji-Tae Lee, Jong-Jun Jang, Yeongjun Kim, Byung Cheol Park, Kyoung Mii Kim, Sunghoon PLoS One Research Article BACKGROUND: Anticancer therapies that target single signal transduction pathways often fail to prevent proliferation of cancer cells because of overlapping functions and cross-talk between different signaling pathways. Recent research has identified that balanced multi-component therapies might be more efficacious than highly specific single component therapies in certain cases. Ideally, synergistic combinations can provide 1) increased efficacy of the therapeutic effect 2) reduced toxicity as a result of decreased dosage providing equivalent or increased efficacy 3) the avoidance or delayed onset of drug resistance. Therefore, the interest in combinatorial drug discovery based on systems-oriented approaches has been increasing steadily in recent years. METHODOLOGY: Here we describe the development of Combinatorial Drug Assembler (CDA), a genomics and bioinformatics system, whereby using gene expression profiling, multiple signaling pathways are targeted for combinatorial drug discovery. CDA performs expression pattern matching of signaling pathway components to compare genes expressed in an input cell line (or patient sample data), with expression patterns in cell lines treated with different small molecules. Then it detects best pattern matching combinatorial drug pairs across the input gene set-related signaling pathways to detect where gene expression patterns overlap and those predicted drug pairs could likely be applied as combination therapy. We carried out in vitro validations on non-small cell lung cancer cells and triple-negative breast cancer (TNBC) cells. We found two combinatorial drug pairs that showed synergistic effect on lung cancer cells. Furthermore, we also observed that halofantrine and vinblastine were synergistic on TNBC cells. CONCLUSIONS: CDA provides a new way for rational drug combination. Together with phExplorer, CDA also provides functional insights into combinatorial drugs. CDA is freely available at http://cda.i-pharm.org. Public Library of Science 2012-08-08 /pmc/articles/PMC3414439/ /pubmed/22905152 http://dx.doi.org/10.1371/journal.pone.0042573 Text en © 2012 Lee et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lee, Ji-Hyun
Kim, Dae Gyu
Bae, Tae Jeong
Rho, Kyoohyoung
Kim, Ji-Tae
Lee, Jong-Jun
Jang, Yeongjun
Kim, Byung Cheol
Park, Kyoung Mii
Kim, Sunghoon
CDA: Combinatorial Drug Discovery Using Transcriptional Response Modules
title CDA: Combinatorial Drug Discovery Using Transcriptional Response Modules
title_full CDA: Combinatorial Drug Discovery Using Transcriptional Response Modules
title_fullStr CDA: Combinatorial Drug Discovery Using Transcriptional Response Modules
title_full_unstemmed CDA: Combinatorial Drug Discovery Using Transcriptional Response Modules
title_short CDA: Combinatorial Drug Discovery Using Transcriptional Response Modules
title_sort cda: combinatorial drug discovery using transcriptional response modules
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414439/
https://www.ncbi.nlm.nih.gov/pubmed/22905152
http://dx.doi.org/10.1371/journal.pone.0042573
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