Translational Proteomics Analysis of Anthracycline-Induced Cardiotoxicity From Cardiac Microtissues to Human Heart Biopsies.

Nhan Nguyen,Nathalie Selevsek,Jos Kleinjans,Hans Gmuender,Terezinha Souza,Ralph Schlapbach,Marcha C T Verheijen,Danyel Jennen

doi:10.3389/fgene.2021.695625

Abstract

Anthracyclines, including doxorubicin, idarubicin, and epirubicin, are common antitumor drugs as well as well-known cardiotoxic agents. This study analyzed the proteomics alteration in cardiac tissues caused by these 3 anthracyclines analogs. The in vitro human cardiac microtissues were exposed to drugs in 2 weeks; the proteomic data were measured at 7 time points. The heart biopsy data were collected from heart failure patients, in which some patients underwent anthracycline treatment. The anthracyclines-affected proteins were separately identified in the in vitro and in vivo dataset using the WGCNA method. These proteins engage in different cellular pathways including translation, metabolism, mitochondrial function, muscle contraction, and signaling pathways. From proteins detected in 2 datasets, a protein-protein network was established with 4 hub proteins, and 7 weighted proteins from both cardiac microtissue and human biopsies data. These 11 proteins, which involve in mitochondrial functions and the NF-κB signaling pathway, could provide insights into the anthracycline toxic mechanism. Some of them, such as HSPA5, BAG3, and SH3BGRL, are cardiac therapy targets or cardiotoxicity biomarkers. Other proteins, such as ATP5F1B and EEF1D, showed similar responses in both the in vitro and in vivo data. This suggests that the in vitro outcomes could link to clinical phenomena in proteomic analysis.

Highlights

Anthracycline (ANT) is a group of well-known chemotherapeutic agents consisting of thousands of analogs; the commonly used analogs are doxorubicin (DOX), epirubicin (EPI), and idarubicin (IDA)
Stock solutions of the drugs were dissolved in 0.1% DMSO, were rectified to their interstitial heart concentrations over time that calculated by reverse physiologically based pharmacokinetic (PBPK) modeling according to dose administration (Kuepfer et al, 2018)
Recent researches on ANTs have explored the ANT-effects on cellular molecules such as DNA (Silva et al, 2017) and RNA (Reyes et al, 2017), but little is known about the ANT effects on the proteome level

Summary

Introduction

Anthracycline (ANT) is a group of well-known chemotherapeutic agents consisting of thousands of analogs; the commonly used analogs are doxorubicin (DOX), epirubicin (EPI), and idarubicin (IDA). IDA, a derivative of Anthracyclines: Microtissues to Heart Biopsies daunorubicin, has shown more potency in antitumor activity, especially, its efficacy in multidrug resistance compared to other ANTs (Kuffel et al, 1992; Minotti et al, 2004). Multiple cohort studies have shown that ANTs exposure dose-dependently increases the risk of cardiac disorder in cancer survivors (Mulrooney et al, 2009; Bates et al, 2019). In order to reduce the cardiac disorder risks, the maximum cumulative doses of DOX and EPI used are recommended to be 450– 600 mg/m2 or 900 mg/m2, respectively (Ryberg et al, 1998; Minotti et al, 2004). In a retrospective study on acute myeloid leukemia and myelodysplasia patients, the probability of IDA-related cardiomyopathy was 5% at a cumulative IDA dose of 150–290 mg/m2 (Anderlini et al, 1995)

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