UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Portugal; LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Portugal.
UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Portugal; Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, Portugal.
Toxicology. 2021 Jul;459:152852. doi: 10.1016/j.tox.2021.152852. Epub 2021 Jul 8.
Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18-20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype.
当前的癌症疗法成功地延长了癌症患者的寿命。然而，心脏毒性是一种严重的化疗诱导的不良反应。阿霉素（DOX）和米托蒽醌（MTX）是具有心脏毒性的抗癌药物，其毒理学机制仍有待确定。本研究侧重于 DOX 和 MTX 对心脏线粒体的损伤及其分子机制。作为一个假设，我们还试图比较 9mg/kg DOX 或 6mg/kg MTX 对年轻成年小鼠（3 个月龄）和老年对照组（年龄对照，18-20 月龄）心脏的调制作用，以确定 DOX 和 MTX 诱导的损伤是否与衰老过程有共同的联系。用 DOX 或 MTX 处理和对照动物制备心脏匀浆和富含线粒体的级分，并通过免疫印迹和酶测定进行分析。还通过基于质谱的蛋白质组学对富含线粒体的级分进行了表征。数据显示，用 DOX 或 MTX 处理的年轻成年小鼠和老年对照组的柠檬酸合酶（CS）活性评估的线粒体密度降低。此外，老年对照组过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC1α）和锰超氧化物歧化酶（MnSOD）的表达增加。关于富含线粒体的级分，DOX 和 MTX 导致与氧化磷酸化、脂肪酸氧化、氨基酸代谢过程和三羧酸循环相关的蛋白质下调。MTX 对苹果酸脱氢酶（MDH2）和丙酮酸脱氢酶 E1 成分亚基α（PDHA1）的影响更大。与年轻对照组相比，老年对照组的富含线粒体级分中未观察到显著的蛋白质组变化。总之，DOX 和 MTX 导致年轻成年小鼠的几种与线粒体相关的蛋白质发生变化，但没有一种类似于老年表型。
