Recovering gap-junction localisation in the heart as a cardioprotective strategy to limit anticancer drug-induced cardiotoxicity.

British Pharmacological Society Summer Studentship.

Cancer survivors often experience heart complications many years after their chemotherapy due to the irreversible damage cancer drugs inflict upon the heart. Animal studies, including the pilot data in this proposal, demonstrates acute cardiotoxicity in the form of ventricular arrhythmia following use of the anti-cancer drug doxorubicin (0.1-1µM). Work carried out by the Cunningham-Currie laboratories have revealed that these events coincide with dysregulation of a critical cardiac gap junction protein, Connexin-43 (Cx43). Preventing Cx43
remodelling may offer a way to protect the heart against anti-cancer drug cardiotoxicity. In a move away from animal models, a three-dimensional (3D) human cardiac spheroid (hCS) model has been established to support with the screening of novel potential cardioprotective small molecules. The aim of the project is to test these small molecules, which have been designed to target Cx43, in the 3D hCS model and compare the pharmacology in Langendorf and left ventricular organ bath experiments. We hypothesize that targeting cardiac Cx43 gap junction proteins to restore normal expression and localisation can protect the heart against doxorubicin-induced cardiotoxicity.