Cardiotoxicity evaluation of anthracyclines in zebrafish (Danio rerio).
Drug-induced cardiotoxicity is a leading factor for drug withdrawals, and limits drug efficacy and clinical use. Therefore, new alternative animal models and methods for drug safety evaluation have been given great attention. Anthracyclines (ANTs) are widely prescribed anticancer agents that have a cumulative dose relationship with cardiotoxicity. We performed experiments to study the toxicity of ANTs in early developing zebrafish embryos, especially their effects on the heart. LC50 values for daunorubicin, pirarubicin, doxorubicin (DOX), epirubicin and DOX-liposome at 72 h post-fertilization were 122.7 μM, 111.9 μM, 31.2 μM, 108.3 μM and 55.8 μM, respectively. At the same time, zebrafish embryos were exposed to ANTs in three exposure stages and induced incomplete looping of the heart tube, pericardia edema and bradycardia in a dose-dependent manner, eventually leading to death. DOX caused the greatest heart defects in the treatment stages and its liposome reduced the effects on the heart, while daunorubicin produced the least toxicity. Genes and proteins related to heart development were also identified to be sensitive to ANT exposure and downregulated by ANTs. It revealed ANTs could disturb the heart formation and development. ANTs induced cardiotoxicity in zebrafish has similar effects in mammalian models, indicating that zebrafish may have a potential value for assessment of drug-induced developmental cardiotoxicity.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Ying
Y
Han
Jing-pu
JP
Zhang
Jian-qin
JQ
Qian
Chang-qin
CQ
Hu
D000818:Animals; D018943:Anthracyclines / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D066126:Cardiotoxicity; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology
D018943:Anthracyclines; D000970:Antineoplastic Agents
alternative animal model; anthracycline; cardiac genes; cardiotoxicity; zebrafish embryo