Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada.
Children's Hospital Research Institute of Manitoba, Winnipeg, Canada.
Toxicol Appl Pharmacol. 2022 Oct 15;453:116210. doi: 10.1016/j.taap.2022.116210. Epub 2022 Aug 24.
Doxorubicin (DOX) is an effective anthracycline used in chemotherapeutic regimens for a variety of haematological and solid tumors. However, its utility remains limited by its well-described, but poorly understood cardiotoxicity. Despite numerous studies describing various forms of regulated cell death and their involvement in DOX-mediated cardiotoxicity, the predominate form of cell death remains unclear. Part of this inconsistency lies in a lack of standardization of in vivo and in vitro model design. To this end, the objective of this study was to characterize acute low- and high-dose DOX exposure on cardiac structure and function in C57BL/6 N mice, and evaluate regulated cell death pathways and autophagy both in vivo and in cardiomyocyte culture models. Acute low-dose DOX had no significant impact on cardiac structure or function; however, acute high-dose DOX elicited substantial cardiac necrosis resulting in diminished cardiac mass and volume, with a corresponding reduced cardiac output, and without impacting ejection fraction or fibrosis. Low-dose DOX consistently activated caspase-signaling with evidence of mitochondrial permeability transition. However, acute high-dose DOX had only modest impact on common necrotic signaling pathways, but instead led to an inhibition in autophagic flux. Intriguingly, when autophagy was inhibited in cultured cardiomyoblasts, DOX-induced necrosis was enhanced. Collectively, these observations implicate inhibition of autophagy flux as an important component of the acute necrotic response to DOX, but also suggest that acute high-dose DOX exposure does not recapitulate the disease phenotype observed in human cardiotoxicity.
多柔比星（DOX）是一种有效的蒽环类药物，用于多种血液系统和实体肿瘤的化疗方案。然而，其应用受到明确但尚未完全理解的心脏毒性的限制。尽管有许多研究描述了各种形式的受调控的细胞死亡及其在 DOX 介导的心脏毒性中的作用，但主要的细胞死亡形式仍不清楚。这种不一致的部分原因在于缺乏体内和体外模型设计的标准化。为此，本研究的目的是描述 C57BL/6N 小鼠中急性低剂量和高剂量 DOX 暴露对心脏结构和功能的影响，并评估受调控的细胞死亡途径和自噬在体内和心肌细胞培养模型中的作用。急性低剂量 DOX 对心脏结构或功能没有显著影响；然而，急性高剂量 DOX 引起了大量的心肌坏死，导致心脏质量和体积减小，心输出量相应降低，而不影响射血分数或纤维化。低剂量 DOX 始终激活半胱氨酸蛋白酶信号，并有证据表明线粒体通透性转换。然而，急性高剂量 DOX 对常见的坏死信号通路只有适度的影响，而是导致自噬通量的抑制。有趣的是，当培养的心肌细胞中的自噬被抑制时，DOX 诱导的坏死增强。总的来说，这些观察结果表明自噬通量的抑制是 DOX 急性坏死反应的一个重要组成部分，但也表明急性高剂量 DOX 暴露并不能再现人类心脏毒性中观察到的疾病表型。
