Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Histology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt.
Life Sci. 2021 Feb 1;266:118822. doi: 10.1016/j.lfs.2020.118822. Epub 2020 Dec 2.
Cyclophosphamide (CYP) is a potent anticancer agent with well-known cardiotoxicity that limits its clinical applications. Cilostazol is a vosodilating drug, showing a cardioprotective effect in some cardiac disorders; however its effect in CYP-induced cardiotoxicity is still uncertain. We investigated the effect of cilostazol against CYP-induced cardiotoxicity and the contribution of SIRT1 signaling.
7 week-old male Wistar albino rats were treated with cilostazol (30 mg/kg/day, orally) in the absence or presence of SIRT1 inhibitor, EX-527 (5 mg/kg/day, IP) for 10 days and injected with CYP (200 mg/kg, IP) on the 7th day of the study. Age-matched rats were used as control group. On the 11th day, hearts were harvested for biochemical, immunoblotting and histological analyses. Markers of cardiac injury were assessed in plasma samples.
CYP injection contributed to cardiac injury manifested as significant increases in plasma activities of heart enzymes and cardiac troponin I levels. Cilostazol attenuated cardiac injury and minimized the histological lesions in hearts of CYP-treated rats. Cilostazol induced 3 fold up-regulation of SIRT1 and promoted the antioxidant defense response through FoxO1-related mechanism in hearts of CYP-treated rats. Cilostazol suppressed the CYP-induced up-regulation of PARP1 and p53, and blocked the NF-kB p65-mediated inflammatory response in hearts of CYP-treated rats. All the beneficial effects of cilostazol were almost abolished by EX-527.
These data provided insights into the mechanism underlying the cardioprotective effect of cilostazol in CYP-treated rats through upregulation of SIRT1 signaling, suggesting that cilostazol might be a candidate modality for CYP-induced cardiotoxicity.
环磷酰胺（CYP）是一种具有明显心脏毒性的强效抗癌药物，限制了其临床应用。西洛他唑是一种血管扩张药物，在某些心脏疾病中显示出心脏保护作用；然而，其在 CYP 诱导的心脏毒性中的作用尚不确定。我们研究了西洛他唑对 CYP 诱导的心脏毒性的作用及其与 SIRT1 信号通路的关系。
7 周龄雄性 Wistar 白化大鼠用西洛他唑（30mg/kg/天，口服）处理，在不存在或存在 SIRT1 抑制剂 EX-527（5mg/kg/天，腹腔注射）的情况下连续处理 10 天，在研究的第 7 天腹腔注射 CYP（200mg/kg）。用年龄匹配的大鼠作为对照组。第 11 天，收获心脏进行生化、免疫印迹和组织学分析。测定血浆样本中心脏损伤标志物。
CYP 注射导致心脏损伤，表现为血浆中心脏酶活性和心肌肌钙蛋白 I 水平显著升高。西洛他唑减轻了 CYP 处理大鼠的心脏损伤并最小化了心脏的组织学损伤。西洛他唑诱导 SIRT1 上调 3 倍，并通过 FoxO1 相关机制促进 CYP 处理大鼠心脏的抗氧化防御反应。西洛他唑抑制了 CYP 诱导的 PARP1 和 p53 的上调，并阻断了 CYP 处理大鼠心脏中的 NF-kB p65 介导的炎症反应。EX-527 几乎消除了西洛他唑的所有有益作用。
这些数据通过 SIRT1 信号通路的上调提供了对西洛他唑在 CYP 处理大鼠中心脏保护作用机制的深入了解，表明西洛他唑可能是 CYP 诱导的心脏毒性的候选治疗方法。
