Doxorubicin (DOX) induced
cardiotoxicity is a life-threatening side effect of
chemotherapy and decreased cardiac function can present years
after treatment. Despite the investigation of a broad range of pharmacologic interventions, to date the only drug shown to reduce DOX-related
cardiotoxicity in preclinical studies and limited clinical trials is the
iron chelating agent,
dexrazoxane (DRZ), although the mechanisms responsible for DRZ mediated protection from DOX related
cardiotoxicity remain unclear. Engineered cardiac tissues (ECTs) can be used for tissue repair strategies and as in vitro surrogate models to test
cardiac toxicities and preventative countermeasures. Neonatal murine ECTs display
cardiotoxicity in response to the environmental toxin,
cadmium, and reduced
cadmium toxicity with
Zinc co-treatment, in part via the induction of the
anti-oxidant Metallothionein (MT). We adapted our in vitro ECT model to determine the feasibility of using the ECT approach to investigate DOX-related cardiac injury and DRZ prevention. We found: (1) DOX induced dose and time dependent cell death in ECTs; (2)
Zinc did not show protection from DOX
cardiotoxicity; (3) MT overexpression induced by
Zinc, low dose Cd pretreatment, or MT-overexpression (MT-TG) did not reduce ECT DOX
cardiotoxicity; (4) DRZ reduced ECT DOX induced cell death; and (5) The mechanism of DRZ ECT protection from DOX
cardiotoxicity was topoisomerase 2B (TOP2B) inhibition rather than reduced
reactive oxygen species. Our data support the feasibility of ECTs as an in vitro platform technology for the investigation of drug induced
cardiotoxicities including the role of TOP2B in DOX toxicity and DRZ mediated DOX toxicity prevention.