Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, 1A Banacha Str., F Building, 02-097 Warsaw, Poland.
Am J Pathol. 2010 Jun;176(6):2658-68. doi: 10.2353/ajpath.2010.090690.
Recent case reports provided alarming signals that treatment with bortezomib might be associated with cardiac events. In all reported cases, patients experiencing cardiac problems were previously or concomitantly treated with other chemotherapeutics including cardiotoxic anthracyclines. Therefore, it is difficult to distinguish which components of the therapeutic regimens contribute to cardiotoxicity. Here, we addressed the influence of bortezomib on cardiac function in rats that were not treated with other drugs. Rats were treated with bortezomib at a dose of 0.2 mg/kg thrice weekly. Echocardiography, histopathology, and electron microscopy were used to evaluate cardiac function and structural changes. Respiration of the rat heart mitochondria was measured polarographically. Cell culture experiments were used to determine the influence of bortezomib on cardiomyocyte survival, contractility, Ca(2+) fluxes, induction of endoplasmic reticulum stress, and autophagy. Our findings indicate that bortezomib treatment leads to left ventricular contractile dysfunction manifested by a significant drop in left ventricle ejection fraction. Dramatic ultrastructural abnormalities of cardiomyocytes, especially within mitochondria, were accompanied by decreased ATP synthesis and decreased cardiomyocyte contractility. Monitoring of cardiac function in bortezomib-treated patients should be implemented to evaluate how frequently cardiotoxicity develops especially in patients with pre-existing cardiac conditions, as well as when using additional cardiotoxic drugs.
最近的病例报告发出了令人震惊的信号，表明硼替佐米治疗可能与心脏事件有关。在所有报告的病例中，出现心脏问题的患者之前或同时接受了其他化疗药物治疗，包括心脏毒性蒽环类药物。因此，很难区分治疗方案的哪些成分导致了心脏毒性。在这里，我们研究了硼替佐米对未接受其他药物治疗的大鼠心脏功能的影响。大鼠以 0.2 毫克/千克的剂量每周三次接受硼替佐米治疗。使用超声心动图、组织病理学和电子显微镜来评估心脏功能和结构变化。使用极谱法测量大鼠心脏线粒体的呼吸。细胞培养实验用于确定硼替佐米对心肌细胞存活、收缩性、Ca(2+)通量、内质网应激和自噬的影响。我们的研究结果表明，硼替佐米治疗导致左心室收缩功能障碍，表现为左心室射血分数显著下降。心肌细胞的超微结构明显异常，尤其是线粒体，伴随着 ATP 合成减少和心肌细胞收缩性降低。应对硼替佐米治疗患者的心脏功能进行监测，以评估心脏毒性的发生频率，特别是在有预先存在的心脏疾病的患者中，以及当使用其他心脏毒性药物时。
