title: Cardiotoxic drugs Herceptin and doxorubicin inhibit cardiac microvascular endothelial cell barrier formation resulting in increased drug permeability.
abstract: Cardiotoxicity 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.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Sherrington Building, Ashton Street, The University of Liverpool, Liverpool, L69 3GE, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Wilkinson
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Sherrington Building, Ashton Street, The University of Liverpool, Liverpool, L69 3GE, UK Molecular Toxicology, AstraZeneca, Alderley Park, Cheshire, SK10 4TG, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Sidaway
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Sherrington Building, Ashton Street, The University of Liverpool, Liverpool, L69 3GE, UK m.j.cross@liv.ac.uk.
authors.forename: Michael J
authors.identifier: http://orcid.org/0000-0002-5533-1232
authors.initials: MJ
authors.lastname: Cross
keywords: Anthracycline; Cardiac permeability; Cardiotoxicity; Endothelial; Herceptin