Karhu, S.T., Kinnunen, S.M., Tölli, M. et al. GATA4-targeted compound exhibits cardioprotective actions against doxorubicin-induced toxicity in vitro and in vivo: establishment of a chronic cardiotoxicity model using human iPSC-derived cardiomyocytes. Arch Toxicol 94, 2113–2130 (2020). https://doi.org/10.1007/s00204-020-02711-8
GATA4-targeted compound exhibits cardioprotective actions against doxorubicin-induced toxicity in vitro and in vivo : establishment of a chronic cardiotoxicity model using human iPSC-derived cardiomyocytes
|Author:||Karhu, S. Tuuli1; Kinnunen, Sini M.1,2; Tölli, Marja2;|
1Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland
2Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland
3National Heart and Lung Institute, Imperial College London, London, UK
|Online Access:||PDF Full Text (PDF, 6.9 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020091769954
|Publish Date:|| 2020-09-17
Doxorubicin is a widely used anticancer drug that causes dose-related cardiotoxicity. The exact mechanisms of doxorubicin toxicity are still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose doxorubicin treatments. Here, we developed an in vitro model of long-term low-dose administration of doxorubicin utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Moreover, given that current strategies for prevention and management of doxorubicin-induced cardiotoxicity fail to prevent cancer patients developing heart failure, we also investigated whether the GATA4-targeted compound 3i-1000 has cardioprotective potential against doxorubicin toxicity both in vitro and in vivo. The final doxorubicin concentration used in the chronic toxicity model in vitro was chosen based on cell viability data evaluation. Exposure to doxorubicin at the concentrations of 1–3 µM markedly reduced (60%) hiPSC-CM viability already within 48 h, while a 14-day treatment with 100 nM doxorubicin concentration induced only a modest 26% reduction in hiPCS-CM viability. Doxorubicin treatment also decreased DNA content in hiPSC-CMs. Interestingly, the compound 3i-1000 attenuated doxorubicin-induced increase in pro-B-type natriuretic peptide (proBNP) expression and caspase-3/7 activation in hiPSC-CMs. Moreover, treatment with 3i-1000 for 2 weeks (30 mg/kg/day, i.p.) inhibited doxorubicin cardiotoxicity by restoring left ventricular ejection fraction and fractional shortening in chronic in vivo rat model. In conclusion, the results demonstrate that long-term exposure of hiPSC-CMs can be utilized as an in vitro model of delayed doxorubicin-induced toxicity and provide in vitro and in vivo evidence that targeting GATA4 may be an effective strategy to counteract doxorubicin-induced cardiotoxicity.
Archives of toxicology
|Pages:||2113 - 2130|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
Open access funding provided by University of Helsinki including Helsinki University Central Hospital. The research was funded by Business Finland (3iRegeneration, project 40395/13), the Academy of Finland (project 2666621), the Finnish Foundation for Cardiovascular Research, and the Sigrid Jusélius Foundation.
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