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 Ca2+-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.ResultsIstaroxime 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 MethodsHuman 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.ConclusionsCombined 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.
Highlights
Prostate cancer (PC) is the most common malignant disease in elderly men in western countries [1]
Functional effects of istaroxime and strophanthidin in human atrial myocardium We assessed the effects of NKA inhibition alone versus NKA inhibition combined with SERCA stimulation on developed force in human atrial trabeculae
Increasing concentrations of istaroxime produced a positive inotropic effect with a maximum effect at 0.3 μM and subsequent force decline at higher concentrations (Figure 1A). Both strophanthidin and istaroxime slightly increased diastolic force compared to baseline in a dose-dependent manner with comparable kinetics of the curves (Figure 1B)
Summary
Prostate cancer (PC) is the most common malignant disease in elderly men in western countries [1]. Novel antiandrogens (enzalutamide) and androgen biosynthesis inhibitors (abiraterone) are approved in the setting of metastatic PC before and after docetaxel chemotherapy. These agents are currently being investigated in clinical trials for their efficacy in a non-metastatic PC setting [5]. Increased risk of cardiovascular diseases, such as coronary artery diseases, acute myocardial infarction and heart failure (HF), are reported as limiting side effects and contraindications for some of these drugs. This may significantly limit their therapeutic use [6,7,8,9,10]
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