Objective

The therapeutic value of vascular disrupting agents (VDAs) as cancer therapeutics is compromised by cardiovascular toxicity. Although VDA-mediated disruption of endothelial cell-cell communication is postulated to cause secondary cardiotoxicity through indirect vascular damage, there is now compelling evidence supporting a direct effect of VDAs upon cardiomyocyte pathophysiology. Clinical and preclinical studies suggest an effect of VDAs upon cardiomyocyte structure, contractility and the molecular basis of these processes. The aim of this project is to determine the molecular basis of VDA-induced cardiotoxicity, and identify pharmacological strategies for mitigation of these life-threatening effects. In this study the AC10 human adult ventricular cell line has been shown to be a viable in vitro model for pathological assessment of drug-induced cardiotoxicity. Colchicine and Combretastatin-A4 both induce growth inhibition in the AC10 cells, in agreement with activity against tubulin. However, cells in the clinically relevant quiescent state also indicate evidence of toxicity, suggesting an alternative toxicity mechanism. Furthermore, VDAs cause changes in cardiomyocyte contraction, implicating a functional as well as structural toxicity mechanism for these drugs. The observation that perturbation of the angiotensin signalling pathway could reduce VDA-mediated cardiotoxicity strongly supports the potential for mitigation of VDA-mediated cardiotoxicity in the clinic.