CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Biocant Park, 3060-197, Cantanhede, Portugal.
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, 55812, USA.
Food Chem Toxicol. 2019 Feb;124:450-461. doi: 10.1016/j.fct.2018.12.017. Epub 2018 Dec 14.
Dose-dependent and cumulative cardiotoxicity associated with doxorubicin (DOX) is the main limitation of anticancer therapy. Pediatric cancer survivors are particularly vulnerable, and no effective prevention measures are available. The aim of the present study was to investigate the persistent effects of nanomolar DOX concentrations and determine whether a pretreatment would induce mitochondrial adaptations in H9c2 cardiomyoblasts. H9c2 cells were incubated with DOX (10 and 25 nM) for 24 h, followed by 9 days of recovery in drug-free medium. We found that the sub-therapeutic DOX treatment induced persistent hypertrophy and dose-dependent cell cycle arrest in G2/M. Glycolytic activity, indirectly based on extracellular acidification rate, and basal respiration were significantly decreased in DOX-treated cells compared to controls, although both groups showed similar maximal respiration. Additionally, nanomolar DOX pretreatment resulted in upregulation of mitochondrial DNA transcripts accompanied by a decrease in DNA methyltransferase 1 (DNMT1) and global methylation levels. Finally, the pretreatment with DOX ameliorated H9c2 cells resistance against a subsequent exposure to DOX. These results suggest that nanomolar DOX pretreatment induced a beneficial and possibly epigenetic-based mitochondrial adaptation, raising the possibility that an early sub-therapeutic DOX treatment can be used as a preconditioning and protective approach during anticancer therapies.
阿霉素（DOX）的剂量依赖性和累积性心脏毒性是癌症治疗的主要限制因素。儿科癌症幸存者尤其容易受到影响，而且目前还没有有效的预防措施。本研究旨在探讨纳摩尔 DOX 浓度的持续作用，并确定预处理是否会诱导 H9c2 心肌细胞中线粒体的适应性改变。将 H9c2 细胞用 DOX（10 和 25 nM）孵育 24 小时，然后在无药物的培养基中恢复 9 天。我们发现，亚治疗剂量的 DOX 处理诱导持续的肥大和剂量依赖性的细胞周期阻滞在 G2/M。与对照组相比，DOX 处理的细胞中糖酵解活性（间接基于细胞外酸化率）和基础呼吸显著降低，尽管两组的最大呼吸相似。此外，纳米 DOX 预处理导致线粒体 DNA 转录物上调，同时 DNA 甲基转移酶 1（DNMT1）和全基因组甲基化水平降低。最后，DOX 的预处理改善了 H9c2 细胞对随后暴露于 DOX 的耐药性。这些结果表明，纳米 DOX 预处理诱导了有益的、可能基于表观遗传的线粒体适应性改变，这使得早期亚治疗剂量的 DOX 治疗有可能成为癌症治疗中的一种预处理和保护方法。
