Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
UCIBIO-Applied Molecular Biosciences Unit, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
Biomolecules. 2021 Nov 19;11(11):1725. doi: 10.3390/biom11111725.
Doxorubicin (DOX) is a topoisomerase II inhibitor commonly used in the treatment of several types of cancer. Despite its efficacy, DOX can potentially cause fatal adverse effects, like cardiotoxicity. This work aimed to assess the role of inflammation in DOX-treated infant and adult mice and its possible link to underlying cardiotoxicity. Two groups of CD-1 male mice of different ages (infants or adults) were subjected to biweekly DOX administrations, to reach a cumulative dose of 18.0 mg/kg, which corresponds approximately in humans to 100.6 mg/m for infants and 108.9 mg/m for adults a clinically relevant dose in humans. The classic plasmatic markers of cardiotoxicity increased, and that damage was confirmed by histopathological findings in both groups, although it was higher in adults. Moreover, in DOX-treated adults, an increase of cardiac fibrosis was observed, which was accompanied by an increase in specific inflammatory parameters, namely, macrophage M1 and nuclear factor kappa B (NF-κB) p65 subunit, with a trend toward increased levels of the tumor necrosis factor receptor 2 (TNFR2). On the other hand, the levels of myeloperoxidase (MPO) and interleukin (IL)-6 significantly decreased in DOX-treated adult animals. In infants, a significant increase in cardiac protein carbonylation and in the levels of nuclear factor erythroid-2 related factor 2 (Nrf2) was observed. In both groups, no differences were found in the levels of tumor necrosis factor (TNF-α), IL-1β, p38 mitogen-activated protein kinase (p38 MAPK) or NF-κB p52 subunit. In conclusion, using a clinically relevant dose of DOX, our study demonstrated that cardiac effects are associated not only with the intensity of the inflammatory response but also with redox response. Adult mice seemed to be more prone to DOX-induced cardiotoxicity by mechanisms related to inflammation, while infant mice seem to be protected from the damage caused by DOX, possibly by activating such antioxidant defenses as Nrf2.
多柔比星（DOX）是一种拓扑异构酶 II 抑制剂，常用于治疗多种类型的癌症。尽管它具有疗效，但 DOX 可能会导致致命的不良反应，如心脏毒性。本研究旨在评估炎症在 DOX 治疗的婴儿和成年小鼠中的作用及其与潜在心脏毒性的可能联系。两组不同年龄（婴儿或成年）的 CD-1 雄性小鼠接受了两周一次的 DOX 给药，累积剂量达到 18.0mg/kg，相当于人类婴儿 100.6mg/m 和成人 108.9mg/m 的临床相关剂量。两组的典型心脏毒性血浆标志物均增加，组织病理学检查也证实了这一点，尽管成年组的损伤更为严重。此外，在 DOX 治疗的成年小鼠中，观察到心脏纤维化增加，这伴随着特定炎症参数的增加，即巨噬细胞 M1 和核因子 kappa B（NF-κB）p65 亚单位，肿瘤坏死因子受体 2（TNFR2）水平也有升高趋势。另一方面，在 DOX 治疗的成年动物中，髓过氧化物酶（MPO）和白细胞介素（IL）-6 的水平显著降低。在婴儿中，观察到心脏蛋白羰基化和核因子红细胞相关因子 2（Nrf2）水平显著增加。在两组中，肿瘤坏死因子（TNF-α）、IL-1β、p38 丝裂原激活蛋白激酶（p38 MAPK）或 NF-κB p52 亚单位的水平均无差异。总之，使用临床相关剂量的 DOX，本研究表明，心脏效应不仅与炎症反应的强度有关，还与氧化还原反应有关。成年小鼠似乎更容易受到 DOX 诱导的心脏毒性的影响，其机制与炎症有关，而婴儿小鼠似乎受到 DOX 引起的损伤的保护，可能是通过激活 Nrf2 等抗氧化防御机制。
