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.

Doxorubicin Induces Endotheliotoxicity and Mitochondrial Dysfunction via ROS/eNOS/NO Pathway

“…As a series of critical pathophysiological events of cardiovascular complications, endothelial dysfunction may cause hemorrhage, infarction, atherosclerosis, restenosis (Soultati et al, 2012;Wojcik et al, 2015). Studies have shown that Dox could downregulate CX40 (Idris-Khodja et al, 2013), MnSOD expression and activity (Koka et al, 2010;Santos-Alves et al, 2019), regulate Bcl-2/Bax ratio (Durrant et al, 2015;You et al, 2019), promote the shift from topoisomerase II a to II b (Deng et al, 2014;Damiani et al, 2018), disturb microRNA, DNA methylation or protein acetylation (Nordgren et al, 2017;Ferreira et al, 2017), affect PARP-2/SIRT (Szántó et al, 2011), VEGF pathway (Chiusa et al, 2012), and interfere with tight junction formation between cardiac microvascular endothelial cells leading to increased permeability (Wilkinson et al, 2016). In the study, we proved in vivo that, after injected Dox with the classical protocol, the mice showed the LDH and CK activities in serum increased significantly (Figures 2A, B), the inflammatory changes were observed by histopathology ( Figure 2C), which was noticeable as brown TUNEL-positive cells in microscopy ( Figure 2D).…”

Beneficial Effects of Systemically Administered Human Muse Cells in Adriamycin Nephropathy

“…DOX has vascular toxicity and causes vessel impairment. 32,33 Nearly one half (approximately 41% for SCID and approximately 47% for BALB/c) of the GFP(+) Muse cells that integrated into the glomeruli expressed endothelial marker CD31(+). Turnover and replacement of endothelial cells are major mechanisms that underlie maintenance of the vascular integrity within the kidney.…”

Oxidative Stress and Cellular Response to Doxorubicin: A Common Factor in the Complex Milieu of Anthracycline Cardiotoxicity

“…Additionally, an appealing concept of cardiac microvascular injury as a potential primary event that contributes to DOX-induced cardiotoxicity has recently emerged. DOX can affect the function of cardiac endothelial cell barrier by affecting the formation of tight junctions thus determining an increased vascular permeability [ 76 ].…”