Cilostazol preconditioning alleviates cyclophosphamide-induced cardiotoxicity in male rats: Mechanistic insights into SIRT1 signaling pathway

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.