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Neonatal Murine Engineered Cardiac Tissue Toxicology Model Impact Of Life Sciences 239 (2019) 117070 Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Neonatal murine engineered cardiac tissue toxicology model: Impact of T dexrazoxane on doxorubicin induced injury ⁎ ⁎⁎ Juan Zhena,b, Haitao Yua,b, Honglei Jia, Lu Caib,c,d, Jiyan Lenga, , Bradley B. Kellerd,e, a The First Hospital of Jilin University, Changchun 130021, China b The Pediatric Research Institute, Department of Pediatrics, the University of Louisville School of Medicine, Louisville, KY 40292, USA c Department of Radiation Oncology, the University of Louisville School of Medicine, Louisville, KY, USA d Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA e Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville School of Medicine, Louisville, KY 40202, USA ARTICLE INFO ABSTRACT Keywords: Doxorubicin (DOX) induced cardiotoxicity is a life-threatening side effect of chemotherapy and decreased car- Cardiotoxicity diac function can present years after treatment. Despite the investigation of a broad range of pharmacologic Dexrazoxane interventions, to date the only drug shown to reduce DOX-related cardiotoxicity in preclinical studies and Doxorubicin limited clinical trials is the iron chelating agent, dexrazoxane (DRZ), although the mechanisms responsible for Engineered cardiac tissue DRZ mediated protection from DOX related cardiotoxicity remain unclear. Engineered cardiac tissues (ECTs) can Metallothionein be used for tissue repair strategies and as in vitro surrogate models to test cardiac toxicities and preventative Topoisomerase 2B Zinc countermeasures. Neonatal murine ECTs display cardiotoxicity in response to the environmental toxin, cad- mium, 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 de- pendent 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 cardio- toxicity; (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 cardi- otoxicities including the role of TOP2B in DOX toxicity and DRZ mediated DOX toxicity prevention. 1. Introduction chemotherapy protocols. However, DOX treatment is associated with late-presenting and progressive cardiotoxicity associated with sig- Over the past 20 years 3-dimensional (3D) ECTs have proven to be a nificant morbidity and mortality [13–17], is of particular risk for pe- robust in vitro platform technology for drug screening [1–63], tissue diatric cancer patients [18], and may have genetic associations repair [2–4], human genetic disease modeling and repair [5–8], and [19–21]. Due to the clinical effectiveness of DOX in chemotherapeutic recently, environmental toxicity [9]. 3D ECTs have multiple advantages protocols for children and adults, multiple strategies have been in- over traditional single cell or monolayer (two-dimensional) culture vestigated to reduce DOX cardiotoxicity. methods including the formation of isotropic and aligned myocardial While limiting the total DOX dose has been shown to reduce the tissues that are electrically and mechanically and function similar to in incidence of cardiotoxicity, pre-clinical investigations of medications vivo myocardium [3,5,10], the ability to customize cell composition to that might prevent DOX induced cardiac injury [22–24] have largely include multiple mesoderm lineages and/or genetically altered cells failed to prevent DOX cardiotoxicity in clinical trials [25]. DOX cardi- [3,5], and the ability to scale up ECT platforms for drug testing [11,12]. otoxicity is mediated, in part, through altered calcium signaling Doxorubicin (DOX), is an anthracycline antibiotic and a topoi- [26,27], mitochondrial iron accumulation [28] and injury [29] which somerase II (TOP2)-targeting drug and is frequently used in increases ROS levels [30], and autophagy [31,32]. Epigenetic variants ⁎ Correspondence to: J. Leng, the First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, China. ⁎⁎ Correspondence to: B. B. Keller, Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, University of Louisville School of Medicine, Louisville, KY 40202, USA. E-mail addresses: [email protected] (J. Leng), [email protected] (B.B. Keller). https://doi.org/10.1016/j.lfs.2019.117070 Received 16 August 2019; Received in revised form 28 October 2019; Accepted 14 November 2019 Available online 18 November 2019 0024-3205/ © 2019 Elsevier Inc. All rights reserved. J. Zhen, et al. Life Sciences 239 (2019) 117070 A DOX (µM) 24hrs C-casp3 17 kDa GAPDH 36 kDa DOX (µM) 48hrs C-casp3 17 kDa GAPDH 36 kDa DOX Dose (µM) B DOX Dose (µM) Fig. 1. Dose and time response of toxic DOX effect on murine ECTs. A, Expression of Cleaved caspase-3 after DOX treatment (0 μM; 0.1 μM; 0.25 μM; 0.5μM;1.0μM) for 24 h and for 48 h; n = 3 to n = 5 ECT per group per time point. B, LDH release after increasing DOX treatment (0 μM; 0.1 μM; 0.25 μM; 0.5 μM; 1.0 μM) for 24 h and for 48 h; n = 3 to n = 5 ECT per group per time point. *P < .05 vs. corresponding normalized Ctrl. Table 1 overexpression reduces DOX cardiotoxicity in vitro [38] and in vivo Dose and time dependent DOX effect on inhibition of ECT beating. ECT beating [39]. The antioxidant flavonoid Apigenin has also been shown tore- was recorded for 15 s following increasing DOX dose (0 μM; 0.1 μM; 0.25 μM; duce DOX cardiotoxicity in rats [40]. Currently, dexrazoxane (DRZ) is 0.5 μM; 1.0 μM) and exposure (12 h, 24 h, 36 h, 48 h, 60 h and 72 h). the only clinically indicated drug used to protect against DOX cardio- Percentage of ECTs with absent beating are displayed, n = 4 to 9 ECT per toxicity [41,42]. The mechanism for the protection has been primarily group. attributed to iron chelation by the EDTA-like hydrolysis of DRZ, which DOX 12 h 24 h 36 h 48 h 60 h 72 h decreases hydroxyl free radicals [43], inhibits Topoisomerase 2B (TOP2B) mediated DNA double-strand breaks [19,44], and reduces 0.0 μM (n = 4) 0 0 0 0 0 0 mitochondrial injury [45]. 0.1 μM (n = 4) 0 0 0 0 0 0 0.25 μM (n = 6) 0 0 0 0 0 33.3% In the current study we tested the hypothesis that in vitro murine 0.5 μM (n = 9) 0 0 11.1% 88.9% 88.9% 100% ECT can rapidly display DOX mediated cardiomyocyte injury and can 1.0 μM (n = 7) 0 85.7% 100% 100% 100% 100% be used to investigate the protective effect of DRZ to reduce DOX toxicity. ECTs displayed rapid and reproducible DOX mediated cardi- otoxicity, no effect of supplemental Zinc to reduce toxicity, andthe ability of DRZ to prevent Dox cardiotoxicity. The DRZ protective effect that increase tolerance for oxidative stress may reduce DOX effective- occurred via TOP2B inhibition rather than changes in ROS. Thus, ness [33,34]. Zinc has been shown in limited preclinical studies to re- neonatal murine ECTs may be a robust and rapid in vitro model to duce DOX induced cardiomyocytes injury via the induction of Nrf2 screen additional compounds with the potential to reduce DOX toxicity [35], as has the anti-oxidant Metallothionein (MT) [36,37] where MT prior to preclinical, in vivo validation. 2 J. Zhen, et al. Life Sciences 239 (2019) 117070 A Ctrl Zn 50µM×24hrs MT 14 kDa GAPDH 36 kDa B 17 kDa 36 kDa 53 kDa C Fig. 2. Zinc induced MT but did not reduce ECT DOX toxicity. A, Zinc (50 μM for 24 h) induced MT expression. n = 3 ECT per group. B, Cleaved caspase-3 expression increased after DOX (0.5 μM for 24 h) and was not reduced by Zinc pretreatment (50 μM for 2 h prior to DOX treatment) and Zinc treatment did not alter baseline cleaved caspase-3. n = 4 to 8 ECT per group. C, Similar to cleaved caspase-3, LDH release increased after DOX (0.5 μM for 24 h) and was not reduced by Zinc pretreatment (50 μM for 2 h prior to DOX treatment) and Zinc treatment did not alter baseline LDH release. n = 4 to 10 ECT per group; *P < .05 and **P < .01 vs. Ctrl ECT. 2. Materials and methods were produced from FVB wild-type (WT) mice obtained from Harlan Bioproducts for Science (Indianapolis, IN) as used in previous studies 2.1. Animals: neonatal wild type and MT-TG mice [9,46]. Both MT-TG and WT mice were housed in the University of Louisville Research Resources Center at 22 °C with a 12-hrs light/dark Cardiac-specific MT gene overexpressing transgenic (MT-TG) mice cycle and were provided free access to standard rodent chow and tap 3 J. Zhen, et al. Life Sciences 239 (2019) 117070 A Cd pretreat DOX MT 14 kDa GPADH 36 kDa B Pretreat with Cd for 2hrs DOX C-casp3 17 kDa GPADH 36 kDa P53 53 kDa Fig. 3. Cadmium pretreatment did not reduce ECT DOX toxicity. A, Cd pretreatment (5 μM for 2 h), but not DOX treatment (0.5 μM for 24 h), induced MT. B, Cd pretreatment (5 μM for 2 h), but not reduce DOX (0.5 μM for 24 h) induced increased cleaved caspase-3 and P53 expression.
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