A new strategy for identifying mechanisms of drug-drug interaction using transcriptome analysis: Compound Kushen Injection as a proof of principle

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dc.contributor.authorShen, H.
dc.contributor.authorQu, Z.
dc.contributor.authorHarata-Lee, Y.
dc.contributor.authorCui, J.
dc.contributor.authorAung, T.N.
dc.contributor.authorWang, W.
dc.contributor.authorKortschak, R.D.
dc.contributor.authorAdelson, D.L.
dc.date.issued2019
dc.descriptionPublished online: 04 November 2019
dc.description.abstractDrug-drug interactions (DDIs), especially with herbal medicines, are complex, making it difficult to identify potential molecular mechanisms and targets. We introduce a workflow to carry out DDI research using transcriptome analysis and interactions of a complex herbal mixture, Compound Kushen Injection (CKI), with cancer chemotherapy drugs, as a proof of principle. Using CKI combined with doxorubicin or 5-Fu on cancer cells as a model, we found that CKI enhanced the cytotoxic effects of doxorubicin on A431 cells while protecting MDA-MB-231 cells treated with 5-Fu. We generated and analysed transcriptome data from cells treated with single treatments or combined treatments and our analysis showed that opposite directions of regulation for pathways related to DNA synthesis and metabolism which appeared to be the main reason for different effects of CKI when used in combination with chemotherapy drugs. We also found that pathways related to organic biosynthetic and metabolic processes might be potential targets for CKI when interacting with doxorubicin and 5-Fu. Through co-expression analysis correlated with phenotype results, we selected the MYD88 gene as a candidate major regulator for validation as a proof of concept for our approach. Inhibition of MYD88 reduced antagonistic cytotoxic effects between CKI and 5-Fu, indicating that MYD88 is an important gene in the DDI mechanism between CKI and chemotherapy drugs. These findings demonstrate that our pipeline is effective for the application of transcriptome analysis to the study of DDIs in order to identify candidate mechanisms and potential targets.
dc.description.statementofresponsibilityHanyuan Shen, Zhipeng Qu, Yuka Harata-Lee, Jian Cui, Thazin N we Aung, Wei Wang, R. Daniel Kortschak & David L. Adelson
dc.identifier.citationScientific Reports, 2019; 9(1):15889-1-15889-12
dc.identifier.doi10.1038/s41598-019-52375-3
dc.identifier.issn2045-2322
dc.identifier.issn2045-2322
dc.identifier.orcidAung, T.N. [0000-0003-4150-0426]
dc.identifier.orcidKortschak, R.D. [0000-0001-8295-2301]
dc.identifier.orcidAdelson, D.L. [0000-0003-2404-5636]
dc.identifier.urihttp://hdl.handle.net/2440/128155
dc.language.isoen
dc.publisherNature Publishing Group
dc.rights© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s41598-019-52375-3
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectFluorouracil
dc.subjectDoxorubicin
dc.subjectDrugs, Chinese Herbal
dc.subjectAntineoplastic Agents
dc.subjectCluster Analysis
dc.subjectGene Expression Profiling
dc.subjectCell Survival
dc.subjectDown-Regulation
dc.subjectUp-Regulation
dc.subjectDrug Interactions
dc.subjectPhenotype
dc.subjectMyeloid Differentiation Factor 88
dc.subjectCell Cycle Checkpoints
dc.titleA new strategy for identifying mechanisms of drug-drug interaction using transcriptome analysis: Compound Kushen Injection as a proof of principle
dc.typeJournal article
pubs.publication-statusPublished

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