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 = 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 tadalafil-treated 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.
Footnotes
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL51045, HL79424, HL93685] (to R.K); an American Heart Association Mid-Atlantic Affiliate Beginning Grant-in-Aid [0765273U] (to A.D.); and an American Heart Association National Scientist Development Grant [0530157N] (to L.X.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.170191.
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ABBREVIATIONS:
- DOX
- doxorubicin
- PDE
- phosphodiesterase
- PKG
- protein kinase G
- SOD
- superoxide dismutase
- Cu/ZnSOD
- cytosolic SOD1
- MnSOD
- mitochondrial SOD2
- LV
- left ventricular
- TUNEL
- terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
- HW/TL
- heart weight/tibia length ratio
- ROS
- reactive oxygen species.
- Received May 12, 2010.
- Accepted June 10, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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