Cardiovascular safety of oncologic agents: A double-edged sword even in the era of targeted therapies – part 1

Introduction: Patients with cancer are subject to the cardiotoxic effects of cancer therapy and as more patients survive cancer due to improved treatment they are exposed to various forms of cardiovascular (CV) disease as they age, and vice-versa. Such an interplay of age with both malignancy and CV disease may contribute to increased morbidity and mortality.

Areas covered: This two-part review considers the effects of cancer drug treatment on the CV system. In Part I, the various types of CV and cardiometabolic toxicity of anti-cancer drugs and the possible mechanisms involved are discussed. Also, among the specific oncologic agents, the CV effects of the classical agents and of the large molecule immunological agents (monoclonal antibodies, including immune checkpoint inhibitors) are detailed.

Expert opinion: Oncologic agents produce a variety of CV adverse effects, including cardiomyopathy and heart failure, peri-myocarditis, coronary artery disease, peripheral vascular disease, hypertension (HTN), cardiac arrhythmias, valvular heart disease, and pulmonary HTN. Both the oncologist and the cardiologist need to be aware of such adverse effects and of the specific agents that produce them. They need to join forces to prevent, anticipate, recognize, and manage such complications.     

Switching cell penetrating and CXCR4-binding activities of nanoscale-organized arginine-rich peptides

Arginine-rich protein motifs have been described as potent cell-penetrating peptides (CPPs) but also as rather specific ligands of the cell surface chemokine receptor CXCR4, involved in the infection by the human immunodeficiency virus (HIV). Polyarginines are commonly used to functionalize nanoscale vehicles for gene therapy and drug delivery, aimed to enhance cell penetrability of the therapeutic cargo. However, under which conditions these peptides do act as either unspecific or specific ligands is unknown. We have here explored the cell penetrability of differently charged polyarginines in two alternative presentations, namely as unassembled fusion proteins or assembled in multimeric protein nanoparticles. By this, we have observed that arginine-rich peptides switch between receptor-mediated and receptor-independent mechanisms of cell penetration. The relative weight of these activities is determined by the electrostatic charge of the construct and the oligomerization status of the nanoscale material, both regulatable by conventional protein engineering approaches.     

Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules

Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.