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A New Strategy for Identifying Mechanisms of Drug-drug Interaction Using Transcriptome Analysis: Compound Kushen
Hanyuan Shen1, Zhipeng Qu1, Yuka Harata-Lee1
1Zhendong Australia - China Centre for Molecular Chinese Medicine, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, 5005, Australia.
Scientific Reports
|November 6, 2019
Summary
This study presents a new workflow for investigating drug-drug interactions (DDIs) involving herbal medicines like Compound Kushen Injection (CKI) and chemotherapy. The research identified MYD88 as a key gene in CKI
Area of Science:
- Pharmacology
- Genomics
- Cancer Biology
Background:
- Drug-drug interactions (DDIs) involving herbal medicines present complex challenges in identifying molecular mechanisms.
- Compound Kushen Injection (CKI) is a complex herbal mixture frequently used in combination therapies.
Purpose of the Study:
- To introduce and validate a workflow for DDI research using transcriptome analysis.
- To investigate the molecular mechanisms of CKI's interactions with chemotherapy drugs, doxorubicin and 5-Fu.
Main Methods:
- Transcriptome analysis of cancer cells treated with single or combined CKI and chemotherapy agents.
- Co-expression analysis correlated with phenotypic outcomes to identify key regulatory genes.
- Validation of candidate genes, specifically MYD88, through functional inhibition.
Main Results:
- CKI demonstrated differential effects, enhancing doxorubicin cytotoxicity in A431 cells and protecting MDA-MB-231 cells from 5-Fu.
- Opposing regulation of DNA synthesis and metabolism pathways explained CKI's varied effects.
- MYD88 was identified as a crucial regulator in the DDI between CKI and 5-Fu, as its inhibition altered cytotoxic effects.
Conclusions:
- The developed workflow effectively utilizes transcriptome analysis to study herbal medicine-chemotherapy DDIs.
- Potential molecular targets, including pathways in organic biosynthesis and metabolism, were identified.
- MYD88 is implicated as a significant factor in the DDI mechanisms between CKI and chemotherapy drugs.
