title: 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 = 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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA.
authors.forename: Saisudha
authors.initials: S
authors.lastname: Koka
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Zhu
authors.forename: David
authors.initials: D
authors.lastname: Durrant
authors.forename: Lei
authors.initials: L
authors.lastname: Xi
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002243:Carbolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000188:drug therapy*; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000627:therapeutic use / Q000633:toxicity*; D050991:GATA4 Transcription Factor / Q000096:biosynthesis; D019254:Genes, bcl-2 / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D032383:Myocytes, Cardiac / Q000187:drug effects; D009368:Neoplasm Transplantation; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000096:biosynthesis; D000068581:Tadalafil; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D002243:Carbolines; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D000068581:Tadalafil; D004317:Doxorubicin; D013482:Superoxide Dismutase; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP