Cardiotoxic drugs Herceptin and doxorubicin inhibit cardiac microvascular endothelial cell barrier formation resulting in increased drug permeability.

Emma L Wilkinson,Michael J Cross,James E Sidaway

doi:10.1242/bio.020362

Emma L Wilkinson, Michael J Cross + Show 1 more

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https://doi.org/10.1242/bio.020362

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Journal: Biology open	Publication Date: Aug 19, 2016
Citations: 78	License type: CC BY 3.0

Affiliation: University of Liverpool

Abstract

ABSTRACTCardiotoxicity induced by anti-cancer therapeutics is a severe, and potentially fatal, adverse reaction of the heart in response to certain drugs. Current in vitro approaches to assess cardiotoxicity have focused on analysing cardiomyocytes. More recently it has become apparent that non-cardiomyocyte cells of the heart can potentially contribute to cardiotoxicity. Herceptin and doxorubicin are known to induce cardiotoxicity in the clinic. The effect of these drugs on the endothelial tight junction barrier was tested by analysing tight junction formation and zona occludens-1 (ZO-1) levels, revealing that Herceptin and doxorubicin are able to induce barrier perturbment and decrease barrier function in human cardiac microvascular endothelial cells (HCMECs) leading to increased permeability. Herceptin treatment had no effect on the tight junction barrier function in human dermal and human brain microvascular endothelial cells. HCMECs showed detectable levels of HER2 compared with the other endothelial cells suggesting that Herceptin binding to HER2 in these cells may interfere with tight junction formation. Our data suggests that doxorubicin and Herceptin can affect tight junction formation in the cardiac microvasculature leading to increased drug permeability and adverse effects on the cardiac myocytes.

Highlights

Cardiotoxicity is defined as a severe and potentially fatal adverse cardiovascular event in response to certain drugs and is responsible for the majority of drug development terminations/withdrawals at the pre-clinical and post-approval stage over the last 10 years (Cross et al, 2015; Laverty et al, 2011)
Using a number of in vitro methods we showed that doxorubicin and Herceptin can affect cardiac microvascular endothelial cell barrier function leading to increased drug permeability
Following the observation that Herceptin reduces tight junction formation and increases permeability in human cardiac microvascular endothelial cells (HCMECs), we investigated the expression of HER2 and HER4 in different endothelial cell types

Summary

Introduction

Cardiotoxicity is defined as a severe and potentially fatal adverse cardiovascular event in response to certain drugs and is responsible for the majority of drug development terminations/withdrawals at the pre-clinical and post-approval stage over the last 10 years (Cross et al, 2015; Laverty et al, 2011). Drug induced cardiotoxicity can result in both functional effects such as arrhythmia and acute alteration of the contractile function (inotropy) of the heart, and morphological (structural) damage to the myocardium (Cross et al, 2015). The cardiac myocardium is composed of cardiomyocytes, which constitute approximately 30% of the total cells, and non-myocytes. (fibroblasts, endothelial cells), which constitute approximately 70% of the total cells (Brutsaert, 2003). Paracellular permeability is regulated by endothelial cell-cell junctions. Adherens junctions initiate cell-to-cell contacts and promote their maturation and maintenance, while tight junctions regulate the passage of ions and solutes through the paracellular route (Bazzoni and Dejana, 2004; González-Mariscal et al, 2005, 2008)

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