Istaroxime, a potential anticancer drug in prostate cancer, exerts beneficial functional effects in healthy and diseased human myocardium

// Markus Wallner 1, 2, * , Mounir Khafaga 1, * , Ewald Kolesnik 1 , Aris Vafiadis 1 , Gerold Schwantzer 3 , Deborah M. Eaton 2 , Pero Curcic 4 , Martin Köstenberger 5 , Igor Knez 4 , Peter P. Rainer 1 , Martin Pichler 6 , Burkert Pieske 1, 7, 8 and Dirk Von Lewinski 1 1 Division of Cardiology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria 2 Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, 19140 PA, United States of America 3 Institute for Medical Informatics, Statistics, and Documentation, Medical University of Graz, 8036 Graz, Austria 4 Division of Cardiac Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria 5 Department of Pediatric Cardiology, Medical University of Graz, 8036 Graz, Austria 6 Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria 7 Department of Internal Medicine and Cardiology, Campus Virchow Klinikum, Charité University Medicine, Berlin, 13353 Berlin, Germany 8 Department of Internal Medicine and Cardiology, German Heart Center, Berlin, 13353 Berlin, Germany * These authors contributed equally to this work Correspondence to: Ewald Kolesnik, email: ewald.kolesnik@medunigraz.at Keywords: prostate cancer, hormone therapy, cardiac disease models, heart failure, istaroxime Received: March 06, 2017      Accepted: April 14, 2017      Published: April 30, 2017 ABSTRACT The current gold standard for prostate cancer treatment is androgen deprivation therapy and antiandrogenic agents. However, adverse cardiovascular events including heart failure can limit therapeutic use. Istaroxime, which combines Na + -K + -ATPase (NKA) inhibition with sarco/endoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) stimulation, has recently shown promising anti-neoplastic effects in prostate cancer (PC) models and may also improve cardiac function. Considering the promising anticancer effects of istaroxime, we aimed to assess its functional effects on human myocardium. Results: Istaroxime and strophanthidin elicited dose-dependent positive inotropic effects with a decline in developed force at supraphysiological concentrations in human atrial, nonfailing, and failing ventricular (ToF) myocardium. Diastolic force and RT50% did not change after exposure to both drugs. The maximal developed force in our in-vitro model of heart failure (ToF) was significantly higher after istaroxime administration. Such a difference did not occur in atrial or nonfailing ventricular trabeculae and was not applicable to the diastolic force. Materials and Methods: Human atrial and ventricular trabeculae were isolated from nonfailing hearts and hearts of infants with tetralogy of Fallot (ToF), which were used as an in-vitro model of heart failure. The samples were electrically stimulated and treated with increasing concentrations of istaroxime and strophanthidin (10 nM–1 μM). Systolic and diastolic force development and relaxation parameters (RT50%) were analyzed. Conclusions: Combined NKA inhibition/SERCA2a stimulation increases contractility in atrial, nonfailing, and failing myocardium. Considering that heart failure is a potential side effect of current PC treatments, especially in elderly patients, istaroxime might combine beneficial cardiac and anti-cancer properties.