Rosuvastatin and simvastatin attenuate cisplatin-induced cardiotoxicity via disruption of endoplasmic reticulum stress-mediated apoptotic death in rats: targeting ER-Chaperone GRP78 and Calpain-1 pathways

Abstract

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.

Curcumin and its derivatives in cancer therapy: Potentiating antitumor activity of cisplatin and reducing side effects

“…Another organ that is negatively affected by CP is the heart. It seems that CP can induce apoptosis and mediate cardiotoxicity via triggering ER stress and up-regulation of GRP78 (Saleh, Mansour, & Mostafa, 2020). Acetyl-l-carnitine was shown to down-regulate caspase-3 expression, while it increased Bcl-2 expression to prevent apoptosis in CP chemotherapy (Bayrak et al, 2020).…”

Rosuvastatin protects PC12 cells from hypoxia/reoxygenation‑induced injury by inhibiting endoplasmic reticulum stress‑induced apoptosis

“…It has also been shown that rosuvastatin may protect endothelial cells from hyperglycemia-induced damage by decreasing ERS ( 18 ). Rosuvastatin and simvastatin attenuate cisplatin-induced cardiotoxicity through the disruption of ERS-mediated apoptotic death in rats via targeting the ER-chaperone GRP78 and calpain-1 pathways ( 30 ). However, the regulatory effect of rosuvastatin on ERS in CIRI has not yet been reported, to the best of our knowledge.…”

Protective effects of melatonin in cisplatin-induced cardiac toxicity: possible role of BDNF-TNF-α signaling pathway

“…XYK20210112. The doses of melatonin 20 , 21 and ANA-12 20 were selected according to previously published studies.…”