Phosphodiesterase‐5 Inhibition with Tadalafil Attenuates Left Ventricular Dysfunction and Cardiomyocyte Apoptosis in Doxorubicin‐induced Cardiotoxicity in Mice

Abstract

Doxorubicin (DOX) is one of the most effective anticancer drugs. However, its cardiotoxicity remains a major clinical concern. As phosphodiesterase‐5 (PDE5) inhibitors are cardioprotective, we hypothesized that tadalafil (TAD), a long acting PDE5 inhibitor, would provide protection against DOX‐induced cardiotoxicity. CF‐1 mice received Saline (0.2 ml ip), DOX (15 mg/kg ip) or DOX+TAD (4 mg/kg po for 9 days; n=18–24/group). Left ventricular (LV) function was assessed by echocardiography and Millar catheter. DOX‐mediated impairment of LV function was significantly reduced by TAD+DOX (p<0.05). Western Blots revealed that DOX‐mediated reduction of Bcl‐2 and GATA‐4 were maintained by TAD+DOX. Antioxidant capacity was also improved through enhanced MnSOD in TAD+DOX. Immunofluorescence staining of Desmin and TUNEL assay showed that DOX‐induced myofibrillar disarray and apoptosis were attenuated by TAD. TAD+DOX significantly increased cGMP level and PKG activity in heart as compared to DOX. Co‐treatment of TAD with DOX did not interfere with the anti‐cancer efficacy of DOX, as determined by human osteosarcoma (OSA‐1) cell viability assay and tumor xenograft model. In conclusion, TAD improved LV function and prevented cardiomyocyte apoptosis via upregulation of cGMP, PKG and MnSOD, without interfering with the chemotherapeutic benefits of DOX. (Supported by NIH HL51045, HL79424, HL93685 & AHA 0765273U)