Review Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond Daniela Di Lisi a , Rosalinda Madonna b,c, ⁎, Concetta Zito d , Enrico Bronte e , Giuseppe Badalamenti e , Paolo Parrella f , Ines Monte g , Carlo Gabriele Tocchetti f , Antonio Russo e , Giuseppina Novo a a Division of Cardiology, Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy b Center of Excellence on Aging, Institute of Cardiology, “G. d'Annunzio” University - Chieti, Chieti, Italy c Texas Heart Institute and University of Texas Medical School in Houston, Cardiology Division, Houston, TX, USA d Cardiology Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy e Department of Surgical, Oncological and Stomatological Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy f Department of Translational Medical Sciences, Division of Internal Medicine, Federico II University, Naples, Italy g Department of General Surgery and Medical-Surgery Specialties, University of Catania, Catania, Italy abstract article info Article history: Received 2 September 2016 Accepted 6 November 2016 Available online 09 November 2016 Cardiotoxicity induced by chemotherapeutic agents and radiotherapy is a growing problem. In recent years, an increasing number of new drugs with targeted action have been designed. These molecules, such as monoclonal antibodies and tyrosine kinase inhibitors, can cause different type of toxicities compared to traditional chemo- therapy. However, they can also cause cardiac complications such as heart failure, arterial hypertension, QT inter- val prolongation and arrhythmias. Currently, a field of intense research is the vascular toxicity induced by new biologic drugs, particularly those which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) and other tyrosine kinases. In this review, we aim at focusing on the problem of vascular toxicity in- duced by new targeted therapies, chemotherapy and radiotherapy, and describe the main mechanisms and em- phasizing the importance of early diagnosis of vascular damage, in order to prevent clinical complications. © 2016 Elsevier Ireland Ltd. All rights reserved. Keywords: Vascular toxicity VEGF Cardiotoxicity New target therapy Chemotherapy Radiotherapy Cardio-oncology 1. Introduction In recent years, with the introduction of new drugs in therapeutic regimens, we have assisted to significant advances in the treatment of cancer. Among these drugs, monoclonal antibodies such as trastuzumab, pertuzumab and bevacizumab, and tyrosine kinase inhibitors-TKI (i.e. sorafenib, sunitinib, imatinib, lapatinib, axitinib, pazopanib, cabozantinib) are often used. Such molecules are characterized by a targeted action [1] on well-known proteins with important roles in can- cer biology [2]. However, despite their selective action, they can still cause cardiovascular complications such as arterial hypertension, QT in- terval prolongation, heart failure (HF), cardiomyopathy, stroke, acute myocardial infarction (AMI), thromboembolic events and cardiovascular deaths [3,4] since the same targets also play a role in maintaining cardio- vascular homeostasis [5–9]. As their effects on the cardiovascular system are not a so-called “class-effect”, for the majority of the approved TKIs the risk of significant cardiotoxicity appears to be low. However, for some of them, this risk can become significant because of their long-term and continued use. Many studies have focused on the myocardial effects of targeted therapies. The purpose of this review is twofold, that is to discuss the major mechanisms of vascular toxicity induced by new targeted thera- pies in parallel with chemotherapy and radiotherapy, and to highlight the importance of an early diagnosis of vascular damage, in order to pre- vent cardiovascular complications. 2. Endothelial function and VEGF It is now well accepted that the endothelium is not a simple cellular monolayer that separates the blood from vascular walls, but also plays a key role in maintaining vascular homeostasis, by producing vasocon- strictor and vasodilator substances, such as endothelin-1 (ET-1), angio- tensin II (Ang II), thromboxane A2, reactive oxygen species, nitrogen monoxide (NO) and prostacyclin [10]. The homeostasis of the entire cardiovascular system is maintained with the help of a healthy endo- thelium. Mature endothelial cells (ECs), endothelial progenitor cells and circulating ECs participate in the physiological maintenance of car- diovascular tissue homeostasis, including vascular tone, permeability and intima thickness, vessel remodeling and angiogenesis, coagulation International Journal of Cardiology 227 (2017) 11–17 ⁎ Corresponding author at: Center of Excellence on Aging, Institute of Cardiology, “G. d'Annunzio” University - Chieti, 66100 Chieti, Italy. E-mail address: rmadonna@unich.it (R. Madonna). http://dx.doi.org/10.1016/j.ijcard.2016.11.174 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved. Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard brought to you by CORE View metadata, citation and similar papers at core.ac.uk provided by Archivio istituzionale della ricerca - Università di Palermo