The First Hospital of Jilin University, Changchun 130021, China; The Pediatric Research Institute, Department of Pediatrics, the University of Louisville School of Medicine, Louisville, KY 40292, USA.
The First Hospital of Jilin University, Changchun 130021, China.
Life Sci. 2019 Dec 15;239:117070. doi: 10.1016/j.lfs.2019.117070. Epub 2019 Nov 18.
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.
阿霉素（DOX）诱导的心脏毒性是化疗的一种危及生命的副作用，并且心脏功能下降可能在治疗后数年出现。尽管已经研究了广泛的药物干预措施，但迄今为止，唯一一种在临床前研究和有限的临床试验中显示可减少 DOX 相关心脏毒性的药物是铁螯合剂地拉佐辛（DRZ），尽管负责 DRZ 介导的 DOX 相关心脏毒性保护的机制仍不清楚。工程心脏组织（ECT）可用于组织修复策略，并作为体外替代模型来测试心脏毒性和预防对策。新生鼠 ECT 对环境毒素镉表现出心脏毒性，并且锌联合治疗可减轻镉毒性，部分原因是诱导抗氧化金属硫蛋白（MT）。我们调整了我们的体外 ECT 模型，以确定使用 ECT 方法研究 DOX 相关心脏损伤和 DRZ 预防的可行性。我们发现：（1）DOX 诱导 ECT 中的剂量和时间依赖性细胞死亡；（2）锌不能预防 DOX 心脏毒性；（3）锌诱导的 MT 过表达、低剂量 Cd 预处理或 MT-TG 过表达不能减轻 ECT DOX 心脏毒性；（4）DRZ 可减少 ECT DOX 诱导的细胞死亡；（5）DRZ 保护 ECT 免受 DOX 心脏毒性的机制是拓扑异构酶 2B（TOP2B）抑制而不是减少活性氧。我们的数据支持 ECT 作为研究药物诱导心脏毒性的体外平台技术的可行性，包括 TOP2B 在 DOX 毒性和 DRZ 介导的 DOX 毒性预防中的作用。
