Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa.
Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa.
Toxicol Appl Pharmacol. 2018 Nov 1;358:86-101. doi: 10.1016/j.taap.2018.06.031. Epub 2018 Jun 30.
Mitochondrial dysfunction is a central element in the development of doxorubicin (DXR)-induced cardiotoxicity. In this context, melatonin is known to influence mitochondrial homeostasis and function. This study aimed to investigate the effects of melatonin on cardiac function, tumor growth, mitochondrial fission and fusion, PGC1-α and sirtuin activity in an acute model of DXR-induced cardiotoxicity. During the in vitro study, H9c2 rat cardiomyoblasts were pre-treated with melatonin (10 μM, 24 h) followed by DXR exposure (3 μM, 24 h). Following treatment, cellular ATP levels and mitochondrial morphology were assessed. In the in vivo study, female Sprague Dawley rats (16 weeks old), were inoculated with a LA7 rat mammary tumor cell line and tumors were measure daily. Animals were injected with DXR (3 × 4 mg/kg) and/or received melatonin (6 mg/kg) for 14 days in their drinking water. Rat hearts were used to conduct isolated heart perfusions to assess cardiac function and thereafter, heart tissue was used for immunoblot analysis. DXR treatment increased cell death and mitochondrial fission which were reduced with melatonin treatment. Cardiac output increased in rats treated with DXR + melatonin compared to DXR-treated rats. Tumor volumes was significantly reduced in DXR + melatonin-treated rats on Day 8 in comparison to DXR-treated rats. Furthermore, DXR + melatonin treatment increased cellular ATP levels, PGC1-α and SIRT1 expression which was attenuated by DXR treatment. These results indicate that melatonin treatment confers a dual cardio-protective and oncostatic effect by improving mitochondrial function and cardiac function whilst simultaneously retarding tumor growth during DXR-induced cardiotoxicity.
线粒体功能障碍是多柔比星（DXR）诱导的心脏毒性发展的核心要素。在这种情况下，褪黑素已知会影响线粒体的动态平衡和功能。本研究旨在探讨褪黑素对急性 DXR 诱导的心脏毒性模型中心脏功能、肿瘤生长、线粒体分裂和融合、PGC1-α 和 SIRT 活性的影响。在体外研究中，用褪黑素（10 μM，24 h）预处理 H9c2 大鼠心肌细胞，然后暴露于 DXR（3 μM，24 h）。处理后，评估细胞内 ATP 水平和线粒体形态。在体内研究中，雌性 Sprague Dawley 大鼠（16 周龄）接种 LA7 大鼠乳腺肿瘤细胞系，每天测量肿瘤大小。动物接受 DXR（3×4 mg/kg）注射，并/或在饮用水中接受褪黑素（6 mg/kg）治疗 14 天。用离体心脏灌流评估大鼠心脏功能，然后用心脏组织进行免疫印迹分析。DXR 处理增加了细胞死亡和线粒体分裂，而褪黑素处理减少了这些变化。与 DXR 处理的大鼠相比，用 DXR+褪黑素处理的大鼠心输出量增加。与 DXR 处理的大鼠相比，DXR+褪黑素处理的大鼠肿瘤体积在第 8 天显著减小。此外，DXR+褪黑素处理增加了细胞内 ATP 水平、PGC1-α 和 SIRT1 的表达，而 DXR 处理则减弱了这种表达。这些结果表明，褪黑素治疗通过改善线粒体功能和心脏功能，同时延缓 DXR 诱导的心脏毒性中的肿瘤生长，发挥双重心脏保护和抗肿瘤作用。
