Abstract

Drug-induced cardiotoxicity usually manifests as heart failure or left ventricular systolic dysfunction. Left ventricular dysfunction is a rarely reported side effect of bevacizumab (BEV) with an incidence of 1.2%, and this occurs irrespective of the route of administration. In this study, we focused on an analysis of BEV effects on mitochondrial complexes activities and protective effect of ellagic acid (EA) against BEV-induced mitochondria toxicity. Rat heart mitochondria were isolated using differential centrifugation form wistar rats. Using biochemical and flowcytometry assays we evaluated mitochondrial complexes activity, succinate dehydrogenases (SDH), mitochondrial swelling, reactive oxygen species (ROS) formation and mitochondrial membrane potential (MMP) in isolated mitochondria. We observed only decreased activity of complexes II after exposure with BEV (50 and 100 µg/ml). The inhibition of complex II is paralleled by the decreased MMP, mitochondrial swelling, and ROS formation. Also, we showed that EA (10–100 µM) as an antioxidant and natural agent significantly decreases mitochondrial toxicity induced by BEV. Together, for the first time, this preliminary study has demonstrated a significant decrease in activity of complexes II after exposure with BEV and proved the protective effects of EA in alleviating BEV-mediated mitochondria toxicity.

摘要

药物引起的心脏毒性通常表现为心力衰竭或左心室收缩功能障碍。左心室功能障碍是贝伐单抗 (BEV) 很少报道的副作用，发生率为 1.2%，无论给药途径如何，都会发生这种情况。在这项研究中，我们重点分析了 BEV 对线粒体复合物活性的影响以及鞣花酸 (EA) 对 BEV 诱导的线粒体毒性的保护作用。使用差速离心从wistar大鼠分离大鼠心脏线粒体。使用生化和流式细胞术测定，我们评估了分离线粒体中的线粒体复合物活性、琥珀酸脱氢酶 (SDH)、线粒体肿胀、活性氧 (ROS) 形成和线粒体膜电位 (MMP)。我们观察到在 BEV（50 和 100 µg/ml）暴露后复合物 II 的活性降低。复合物 II 的抑制与 MMP 减少、线粒体肿胀和 ROS 形成平行。此外，我们还发现 EA (10–100 µM) 作为抗氧化剂和天然药剂可显着降低 BEV 诱导的线粒体毒性。总之，这项初步研究首次证明了与 BEV 接触后复合物 II 的活性显着降低，并证明了 EA 在减轻 BEV 介导的线粒体毒性方面的保护作用。