Abstract：
: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.
journal_name
Life Scijournal_title
Life sciencesauthors
Zhen J,Yu H,Ji H,Cai L,Leng J,Keller BBdoi
10.1016/j.lfs.2019.117070subject
Has Abstractpub_date
2019-12-15 00:00:00pages
117070eissn
0024-3205issn
1879-0631pii
S0024-3205(19)30997-Xjournal_volume
239pub_type
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