Protective effect of cilostazol against doxorubicin-induced cardiomyopathy in mice

• Published in: Free radical biology & medicine 2015-12, Vol.89, p.54-61
• Main Authors: Koh, Jin Sin, Yi, Chin-ok, Heo, Rok Won, Ahn, Jong-Wha, Park, Jeong Rang, Lee, Jung Eun, Kim, Jung-Hwan, Hwang, Jin-Yong, Roh, Gu Seob
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - toxicity; Blotting, Western; Cardiomyopathies - chemically induced; Cardiomyopathies - pathology; Cardiomyopathies - prevention & control; Cardiomyopathy; Cilostazol; Doxorubicin; Doxorubicin - toxicity; Echocardiography; Fibrosis - chemically induced; Fibrosis - pathology; Fibrosis - prevention & control; Free radicals; Inflammation - chemically induced; Inflammation - pathology; Inflammation - prevention & control; Male; Mice; Mice, Inbred ICR; Mouse; Neuroprotective Agents - pharmacology; Oxidative Stress - drug effects; Tetrazoles - pharmacology
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2015.07.016

Doxorubicin (Dox) is an effective anti-cancer drug, but its use is limited because of its adverse effect of inducing irreversible dilated cardiomyopathy. Cilostazol (Cilo), a potent phosphodiesterase III inhibitor, has been reported to have an anti-inflammatory effect. Here, we investigated whether Cilo has a protective effect against Dox-induced cardiomyopathy (DIC). Mice were randomly divided into four groups: saline control, Dox (15mg/kg), Dox (15mg/kg) plus Cilo (50mg/kg), and Cilo (50mg/kg). The results showed that the coadministration of Dox and Cilo significantly enhanced left-ventricular systolic function compared with Dox alone. In addition, Cilo treatment significantly reduced Dox-induced perivascular fibrosis, collagen concentration, and connective growth factor expression in the heart. Also, Cilo administration markedly reduced Dox-induced levels of serum B-type natriuretic peptide, dysferlin, high-mobility group protein B1, Toll-like receptor 4, nuclear factor-κB p65, and cyclooxygenase-2. Furthermore, Cilo treatment significantly reduced Dox-induced oxidative stress by lowering the translocation of Nrf2 into the nucleus and the expression of NQO1, heme oxygenase 1, and superoxide dismutase-1. Our results suggest that Cilo may be a potential antifibrotic, antioxidative, and anti-inflammatory drug for DIC. •Doxorubicin decreases systolic function of the left ventricle.•Cilostazol, a potent phosphodiesterase III inhibitor, protects against doxorubicin-induced cardiomyopathy.•Cilostazol has anti-inflammatory, antifibrotic, and antioxidative effects in doxorubicin-treated hearts.