Saleh Dalia O, Mansour Dina F, Mostafa Rasha E
Department of Pharmacology, National Research Centre (ID: 60014618), 33 El Buhouth st-Dokki P.O:12622, Cairo, Egypt.
Toxicol Rep. 2020 Sep 12;7:1178-1186. doi: 10.1016/j.toxrep.2020.08.026. eCollection 2020.
Cisplatin (CP) is a powerful antineoplastic chemotherapeutic agent with broad-spectrum properties. Acute and cumulative cardiotoxicity are major limiting factors for CP therapy. Various pathogenic pathways have been suggested to CP-induced cardiotoxicity; oxidative damage, ER stress, and programmed cell death/apoptosis. The present study aimed to assess the signaling mechanisms related to the advantageous effects of rosuvastatin (RSV) and simvastatin (SMV) against CP-related cardiac ER stress dependent apoptotic death in rats. Acute cardiotoxicity was induced by a single dose of CP (10 mg/kg, i.p.) on the 10th day of the experiment. RSV (10 mg/ kg/day) and SMV (10 mg/kg/day) were orally administered for 15 days. CP-treated rats showed significant alterations in electrocardiographic recordings and elevation in serum cardiac function biomarkers; troponin T content, lactate dehydrogenase and creatine kinase-MB levels as well as boost in the cardiac oxidative stress biomarkers. In addition, CP exposure resulted in GRP78 induction; an ER stress and elevation marker at calpain-1 content as well as activation of activated caspase-3 (ACASP3) and caspase-12 were reflected on CP-triggered apoptosis evidenced by elevation in the Bax/Bcl-2 ratio. However, RSV and SMV administration mitigate those adverse CP effects. Statins administration prominently alleviated CP-induced cardiac abnormalities exerting improvement in the ECG pattern and cardiac enzyme biomarkers. Interestingly, statins; RSV and SMV, disrupted CP-induced ER stress and the consequent apoptotic cell death evidenced by downregulation of ER-chaperone GRP78, calpain-1, ACASP3 and caspase-12 as well as decline in the Bax/Bcl-2 ratio. From all the previous findings, it can be suggested that statins namely; RSV and SMV, play protective role against CP-induced cardiac injury by regulating ER stress-mediated apoptotic pathways.
顺铂（CP）是一种具有广谱特性的强效抗肿瘤化疗药物。急性和累积性心脏毒性是CP治疗的主要限制因素。已提出多种致病途径与CP诱导的心脏毒性有关；氧化损伤、内质网应激和程序性细胞死亡/凋亡。本研究旨在评估瑞舒伐他汀（RSV）和辛伐他汀（SMV）对大鼠CP相关心脏内质网应激依赖性凋亡死亡的有利影响的信号传导机制。在实验的第10天，通过单次腹腔注射CP（10 mg/kg）诱导急性心脏毒性。RSV（10 mg/kg/天）和SMV（10 mg/kg/天）口服给药15天。CP处理的大鼠心电图记录出现显著改变，血清心脏功能生物标志物升高；肌钙蛋白T含量、乳酸脱氢酶和肌酸激酶-MB水平以及心脏氧化应激生物标志物升高。此外，CP暴露导致GRP78诱导；内质网应激和钙蛋白酶-1含量升高标志物以及活化的半胱天冬酶-3（ACASP3）和半胱天冬酶-12的活化反映在CP触发凋亡上，这通过Bax/Bcl-2比值升高得以证明。然而，RSV和SMV给药减轻了CP的这些不良影响。他汀类药物给药显著减轻了CP诱导的心脏异常，使心电图模式和心脏酶生物标志物得到改善。有趣的是，他汀类药物；RSV和SMV，破坏了CP诱导的内质网应激以及随之而来的凋亡细胞死亡，这通过内质网伴侣GRP78、钙蛋白酶-1、ACASP3和半胱天冬酶-12的下调以及Bax/Bcl-2比值下降得以证明。从所有先前的研究结果可以看出，他汀类药物即RSV和SMV，通过调节内质网应激介导的凋亡途径对CP诱导的心脏损伤起到保护作用。
