Abstract

Cardiotoxicity is a major cause of drug attrition and life-threatening complication of many
anticancer therapies. Current preclinical methodologies for identification of drug-induced
structural and/or functional cardiotoxicity and their underlying mechanism are sub-optimal,
involving either non cardiac cell lines expressing specific ion channels, or ex-vivo cardiac
tissues with limited utility for longer-term analyses and clinical translation. The emergence
of innovative technologies combined with the use of human induced pluripotent stem cellderived cardiomyocytes (hiPSC-CM), with the ability to synchronously contract in-vitro,
revolutionised identification of drug-induced cardiotoxicity. However, major limitations to
this approach are their complexity, specialised culture conditions, high cost and
subsequent limitations for assessment of drug-induced cardiotoxicity. One resolution is
incorporation of cardiac cell lines into the initial screening paradigm. The study objective
was to evaluate the responsiveness of current cardiac cell-lines to both structural and
functional cardiotoxicants, specifically the human ventricular cardiomyocyte cell-line, AC10,
and the murine atrial cell-line, HL-1, relative to both primary neonatal rodent
cardiomyocytes and hiPSC-CM. Real-time assessment of pathophysiological changes
were determined by impedance-based in vitro methodologies (xCELLigence RTCA), with
known cardiac therapeutics and the histone deacetylase inhibitor (HDACi) class of drugs
being evaluated in this context. The AC10 cell-line, although non-contractile, was able to
detect drug-induced structural changes. The HL-1 cell-line was also able to detect
structural cardiotoxicants, and exhibited a contractile phenotype in vitro, albeit nonuniformally and time-limited. This study indicates there is scope for inclusion of cardiac
cell-lines alongside primary cells and hiPSC-CM in preclinical evaluation of drug-induced
cardiotoxicity.