Long-Acting Phosphodiesterase-5 Inhibitor Tadalafil Attenuates Doxorubicin-Induced Cardiomyopathy without Interfering with Chemotherapeutic Effect

Abstract

Doxorubicin (DOX) is one of the most effective anticancer drugs. However, its cardiotoxicity remains a clinical concern that severely restricts its therapeutic usage. We designed this study to investigate whether tadalafil, a long-acting phosphodiesterase-5 (PDE-5) inhibitor, protects against DOX-induced cardiotoxicity. We also sought to delineate the cellular and molecular mechanisms underlying tadalafil-induced cardioprotection. Male CF-1 outbred mice were randomized into three groups (n ϭ 15-24/group) to receive either saline (0.2 ml i.p.), DOX (15 mg/kg, given by a single intraperitoneal injection), or tadalafil (4 mg/kg p.o. daily for 9 days) plus DOX. Left ventricular function was subsequently assessed by transthoracic echocardiography and Millar conductance catheter. Cardiac contractile function was impaired by DOX, and it was significantly improved by cotreatment with tadalafil. Tadalafil attenuated DOX-induced apoptosis and depletion of prosurvival proteins, including Bcl-2 and GATA-4, in myocardium. Cardiac oxidative stress was attenuated and antioxidant capacity was enhanced by tadalafil possibly via up-regulation of mitochondrial superoxide dismutase (MnSOD). Moreover, the tadalafiltreated group demonstrated increased cardiac cGMP level and protein kinase G (PKG) activity. Tadalafil did not interfere with the efficacy of DOX in killing human osteosarcoma cells in vitro or its antitumor effect in vivo in tumor xenograft model. We conclude that tadalafil improved left ventricular function and prevented cardiomyocyte apoptosis in DOX-induced cardiomyopathy through mechanisms involving up-regulation of cGMP, PKG activity, and MnSOD level without interfering with the chemotherapeutic benefits of DOX.

The Role of PDE-5 Inhibitors in Prostate Cancer

“…Additionally, the antiapoptotic protein Bcl-2 was significantly declined after treatment in the DOX group compared with the sildenafil + DOX and control groups, suggesting a pivotal role of Bcl-2 in altering the pathological process leading to end-stage heart failure. More recently, we showed that tadalafil, the long acting PDE-5 inhibitor, also improved LV function by preserving fractional shortening (LVFS) and ejection fraction (LVEF) compared with DOX-treated mice (Figure 2) (Koka et al, 2010). This study also demonstrated that tadalafil improved survival rates in mice without interfering with the anti-tumor effect of DOX.…”

Oxidative Stress Induced by Ureteral Obstruction and Tadalafil

“…Hücrede cGMP (siklik guanozin monofosfat) yıkımını engelleyen ve stoplazmik cGMP konsantrasyonunu arttırarak etkisini göste-ren bu grup ilaçların anti-oksidan etkilerini gösteren çalışmalar da vardır (14)(15)(16)(17)(18)(19)(20)(21)(22). Farklı dozlarda ve farklı sürelerde uygulanan PDE5 inhibitörlerinin; diyabet (14,15), iskemi-reperfüzyon (16)(17)(18), pulmoner hipertansiyon (19,20) ve kardiyomiyopati (21) gibi deneysel modellerde kalp, böbrek, over ve kavernöz dokularda oksidatif stresi azaltıp fonksiyonel iyileşme sağladığı gösterilmiştir.…”

Phosphodiesterase-5 Inhibitors Improve Left Ventricular Function in Failing Hearts

“…A number of pioneering investigations from our laboratory have demonstrated that PDE-5 inhibitors attenuate doxorubicin-induced cardiomyopathy in animal and cell models (Koka et al, 2010;Das et al, 2010). In a recent study, we tested whether sildenafil potentiates the antitumor efficacy of doxorubicin in prostate cancer.…”

“…In a separate study, tadalafil improved left ventricular function and prevented cardiomyocyte apoptosis in doxorubicin-induced cardiomyopathy through mechanisms involving upregulation of cGMP, PKG activity, and MnSOD level without interfering with the chemotherapeutic benefits of doxorubicin (Koka et al, 2010). In these studies, adult male CF-1 mice were randomized to receive saline (0.2 ml i.p.…”