Metformin and/or low dose radiation reduces cardiotoxicity and apoptosis induced by cyclophosphamide through SIRT-1/SOD and BAX/Bcl-2 pathways in rats

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