Cyclophosphamide (CP) is a nitrogen mustard alkylating agent with effective antineoplastic, immunomodulatory and immunosuppressive properties. Despite its vast therapeutic uses, it is known to trigger strict cardiac toxicity. The objective of the current study was to examine the protective role of metformin (MET) and/or low dose radiation (LDR) on cardiotoxicity and apoptosis induced by CP in rats. CP (200 mg/kg i.p) induces cardiotoxicity and apoptosis as indicated by elevation of troponin, cardiac caspase-3 and Endothelin-I (ET-1). While, treatment with MET (150 mg/kg, orally for 14 days) and/or LDR (0.5 Gy) before CP hindered CP-induced toxicity. By estimating the apoptotic index (BAX/Bcl-2 ratio) CP showed significantly the highest BAX/Bcl-2 ratio. Administration of MET and/or LDR showed a significant improvement in oxidative stress indices and reverse the inhibitory effect of CP on SIRT-1. Also, Histological examination of cardiac tissues showed a sign of necrosis of myocardium after CP treatment. Conclusions: The results revealed that MET and/or LDR attenuate CP-induced cardiotoxicity by inhibiting oxidative stress and preserving the activity of antioxidant enzymes through SIRT-1/SOD and BAX/Bcl-2 pathways.

Graphic abstract

中文翻译：

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二甲双胍和/或低剂量辐射通过大鼠的SIRT-1 / SOD和BAX / Bcl-2途径降低了环磷酰胺诱导的心脏毒性和细胞凋亡。

环磷酰胺（CP）是氮芥子烷基化剂，具有有效的抗肿瘤，免疫调节和免疫抑制特性。尽管有广泛的治疗用途，但已知会引发严格的心脏毒性。本研究的目的是研究二甲双胍（MET）和/或低剂量辐射（LDR）对大鼠CP引起的心脏毒性和细胞凋亡的保护作用。CP（200 mg / kg ip ip）诱导心肌毒性和凋亡，如肌钙蛋白，心脏caspase-3和内皮素I（ET-1）升高所表明。同时，在CP之前用MET（150 mg / kg，口服治疗14天）和/或LDR（0.5 Gy）治疗会阻碍CP诱导的毒性。通过估计细胞凋亡指数（BAX / Bcl-2比），CP表现出最高的BAX / Bcl-2比。MET和/或LDR的使用显示出氧化应激指数的显着改善，并逆转了CP对SIRT-1的抑制作用。同样，对心脏组织的组织学检查显示，CP治疗后心肌坏死的迹象。结论：结果表明，MET和/或LDR通过SIRT-1 / SOD和BAX / Bcl-2途径抑制氧化应激并保留抗氧化酶的活性，从而减轻CP引起的心脏毒性。

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