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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.<\/jats:p>","DOI":"10.1038\/s41598-019-52375-3","type":"journal-article","created":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T06:03:55Z","timestamp":1572847435000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A New Strategy for Identifying Mechanisms of Drug-drug Interaction Using Transcriptome Analysis: Compound Kushen Injection as a Proof of Principle"],"prefix":"10.1038","volume":"9","author":[{"given":"Hanyuan","family":"Shen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Harata-Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4150-0426","authenticated-orcid":false,"given":"Thazin Nwe","family":"Aung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work. While a generous donation was used to set up the Zhendong Centre by Shanxi Zhendong Pharmaceutical Co Ltd, they did not determine the research direction for this work or influence the analysis of the data. J.C.: no competing interests, Z.Q.: no competing interests, Y.H.L.: no competing interests, H.S.: no competing interests, T.N.A.: no competing interests, W.W.: is an employee of Zhendong Pharma seconded to Zhendong Centre to learn bioinformatics methods, R.D.K.: no competing interests, D.L.A.:Director of the Zhendong Centre which was set up with a generous donation from the Zhendong Pharmaceutical Co Ltd. Zhendong Pharmaceutical has had no control over these experiments, their design or analysis and have not exercised any editorial control over the manuscript.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15889"}}