Department of Cardiology, Peking University Third Hospital, Beijing, China.
Department of Respiration, The Affiliated Hospital of Qingdao University, Qingdao, China.
J Cell Mol Med. 2019 Jul;23(7):4627-4639. doi: 10.1111/jcmm.14346. Epub 2019 May 20.
Doxorubicin (DOX) is widely used to treat various cancers affecting adults and children; however, its clinical application is limited by its cardiotoxicity. Previous studies have shown that children are more susceptible to the cardiotoxic effects of DOX than adults, which may be related to different maturity levels of cardiomyocyte, but the underlying mechanisms are not fully understood. Moreover, researchers investigating DOX-induced cardiotoxicity caused by human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have shown that dexrazoxane, the recognized cardioprotective drug for treating DOX-induced cardiotoxicity, does not alleviate the toxicity of DOX on hiPSC-CMs cultured for 30 days. We have suggested that this may be ascribed to the immaturity of the 30 days hiPSC-CMs. In this study, we investigated the mechanisms of DOX induced cardiotoxicity in cardiomyocytes of different maturity. We selected 30-day-old and 60-day-old hiPSC-CMs (day 30 and day 60 groups), which we term 'immature' and 'relatively mature' hiPSC-CMs, respectively. The day 30 CMs were found to be more susceptible to DOX than the day 60 CMs. DOX leads to more ROS (reactive oxygen species) production in the day 60 CMs than in the relatively immature group due to increased mitochondria number. Moreover, the day 60 CMs mainly expressed topoisomerase IIβ presented less severe DNA damage, whereas the day 30 CMs dominantly expressed topoisomerase IIα exhibited much more severe DNA damage. These results suggest that immature cardiomyocytes are more sensitive to DOX as a result of a higher concentration of topoisomerase IIα, which leads to more DNA damage.
多柔比星（DOX）被广泛用于治疗成人和儿童的各种癌症；然而，其临床应用受到其心脏毒性的限制。先前的研究表明，儿童比成人更容易受到 DOX 的心脏毒性影响，这可能与心肌细胞的不同成熟水平有关，但潜在的机制尚不完全清楚。此外，研究人员研究了人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）中 DOX 诱导的心脏毒性，结果表明，多柔比星心脏毒性的公认保护药物右雷佐生不能减轻培养 30 天的 hiPSC-CMs 中 DOX 的毒性。我们认为这可能归因于培养 30 天的 hiPSC-CMs 的不成熟。在这项研究中，我们研究了不同成熟度的心肌细胞中 DOX 诱导的心脏毒性的机制。我们选择了 30 天龄和 60 天龄的 hiPSC-CMs（第 30 天和第 60 天组），分别称为“不成熟”和“相对成熟”的 hiPSC-CMs。结果发现，第 30 天的 CMs 比第 60 天的 CMs 对 DOX 更敏感。由于线粒体数量增加，DOX 导致第 60 天的 CMs 产生更多的 ROS（活性氧）。此外，第 60 天的 CMs 主要表达拓扑异构酶 IIβ，表现出较少的 DNA 损伤，而第 30 天的 CMs 主要表达拓扑异构酶 IIα，表现出更严重的 DNA 损伤。这些结果表明，由于较高浓度的拓扑异构酶 IIα，不成熟的心肌细胞对 DOX 更为敏感，从而导致更多的 DNA 损伤。
