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Toxicol Lett. 2018 Sep 15;294:184-192. doi: 10.1016/j.toxlet.2018.05.029. Epub 2018 May 24.

Bringing in vitro analysis closer to in vivo: Studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling.

Author information

1
Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands. Electronic address: marcha.verheijen@maastrichtuniversity.nl.
2
Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands.
3
Genedata AG, Basel, Switzerland.
4
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
5
Luxcel Biosciences Ltd, Cork, Ireland.
6
Department of Imaging Sciences and BioMedical Engineering, King's College London, London, UK.
7
Institute of Applied Microbiology, RWTH, Aachen, Germany.

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent of which the medical use is limited due to cardiotoxicity. While acute cardiotoxicity is reversible, chronic cardiotoxicity is persistent or progressive, dose-dependent and irreversible. While DOX mechanisms of action are not fully understood yet, 3 toxicity processes are known to occur in vivo: cardiomyocyte dysfunction, mitochondrial dysfunction and cell death. We present an in vitro experimental design aimed at detecting DOX-induced cardiotoxicity by obtaining a global view of the induced molecular mechanisms through RNA-sequencing. To better reflect the in vivo situation, human 3D cardiac microtissues were exposed to physiologically-based pharmacokinetic (PBPK) relevant doses of DOX for 2 weeks. We analysed a therapeutic and a toxic dosing profile. Transcriptomics analysis revealed significant gene expression changes in pathways related to "striated muscle contraction" and "respiratory electron transport", thus suggesting mitochondrial dysfunction as an underlying mechanism for cardiotoxicity. Furthermore, expression changes in mitochondrial processes differed significantly between the doses. Therapeutic dose reflects processes resembling the phenotype of delayed chronic cardiotoxicity, while toxic doses resembled acute cardiotoxicity. Overall, these results demonstrate the capability of our innovative in vitro approach to detect the three known mechanisms of DOX leading to toxicity, thus suggesting its potential relevance for reflecting the patient situation. Our study also demonstrated the importance of applying physiologically relevant doses during toxicological research, since mechanisms of acute and chronic toxicity differ.

KEYWORDS:

3D microtissues; Cardiotoxicity; Doxorubicin; Mitochondrial dysfunction; Physiologically-based pharmacokinetic modeling; Transcriptomics

PMID:
29803840
DOI:
10.1016/j.toxlet.2018.05.029
[Indexed for MEDLINE]
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