Systems Biology Research Center, School of Bioscience, University of Skövde, Box 408, Kanikegränd 3A, SE-541 28 Skövde, Sweden; Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
Systems Biology Research Center, School of Bioscience, University of Skövde, Box 408, Kanikegränd 3A, SE-541 28 Skövde, Sweden.
Toxicology. 2015 Feb 3;328:102-11. doi: 10.1016/j.tox.2014.12.018. Epub 2014 Dec 18.
Doxorubicin is a chemotherapeutic agent indicated for the treatment of a variety of cancer types, including leukaemia, lymphomas, and many solid tumours. The use of doxorubicin is, however, associated with severe cardiotoxicity, often resulting in early discontinuation of the treatment. Importantly, the toxic symptoms can occur several years after the termination of the doxorubicin administration. In this study, the toxic effects of doxorubicin exposure have been investigated in cardiomyocytes derived from human embryonic stem cells (hESC). The cells were exposed to different concentrations of doxorubicin for up to 2 days, followed by a 12 day recovery period. Notably, the cell morphology was altered during drug treatment and the cells showed a reduced contractile ability, most prominent at the highest concentration of doxorubicin at the later time points. A general cytotoxic response measured as Lactate dehydrogenase leakage was observed after 2 days' exposure compared to the vehicle control, but this response was absent during the recovery period. A similar dose-dependant pattern was observed for the release of cardiac specific troponin T (cTnT) after 1 day and 2 days of treatment with doxorubicin. Global transcriptional profiles in the cells revealed clusters of genes that were differentially expressed during doxorubicin exposure, a pattern that in some cases was sustained even throughout the recovery period, suggesting that these genes could be used as sensitive biomarkers for doxorubicin-induced toxicity in human cardiomyocytes. The results from this study show that cTnT release can be used as a measurement of acute cardiotoxicity due to doxorubicin. However, for the late onset of doxorubicin-induced cardiomyopathy, cTnT release might not be the most optimal biomarker. As an alternative, some of the genes that we identified as differentially expressed after doxorubicin exposure could serve as more relevant biomarkers, and may also help to explain the cellular mechanisms behind the late onset apoptosis associated with doxorubicin-induced cardiomyopathy.
多柔比星是一种化疗药物，适用于治疗多种癌症类型，包括白血病、淋巴瘤和许多实体瘤。然而，多柔比星的使用与严重的心脏毒性相关，常导致治疗提前终止。重要的是，毒性症状可能在多柔比星给药结束后数年出现。在这项研究中，研究了来源于人胚胎干细胞（hESC）的心肌细胞中多柔比星暴露的毒性作用。细胞暴露于不同浓度的多柔比星中长达 2 天，随后进行 12 天的恢复期。值得注意的是，在药物治疗过程中细胞形态发生改变，并且细胞的收缩能力降低，在最高浓度的多柔比星和稍后的时间点最为明显。与载体对照相比，在 2 天暴露后观察到乳酸脱氢酶漏出导致的一般细胞毒性反应，但在恢复期内不存在该反应。在 1 天和 2 天的多柔比星处理后，心肌肌钙蛋白 T（cTnT）的释放也观察到类似的剂量依赖性模式。细胞中的全局转录谱显示出在多柔比星暴露期间差异表达的基因簇，在某些情况下，这种模式甚至在整个恢复期内都持续存在，表明这些基因可作为人心肌细胞中多柔比星诱导毒性的敏感生物标志物。这项研究的结果表明，cTnT 的释放可用于测量由于多柔比星引起的急性心脏毒性。然而，对于多柔比星诱导的心肌病的迟发性发病，cTnT 的释放可能不是最佳的生物标志物。作为替代方案，我们在多柔比星暴露后鉴定出的一些差异表达的基因可以作为更相关的生物标志物，并且可能有助于解释与多柔比星诱导的心肌病相关的迟发性细胞凋亡的细胞机制。
