Sotalol, but not digoxin is associated with decreased prostate cancer risk: A population‐based case–control study

Abstract

Antiarrhythmic drug digoxin has been reported to have apoptosis-inducing and cytotoxic effects on prostate cancer cells. We evaluated the association between antiarrhythmic drug use and prostate cancer risk in a population-based case-control study. The study included all new prostate cancer cases diagnosed in Finland during 1995-2002 and matched controls (24,657 casecontrol pairs) obtained from the Finnish Cancer Registry and the Population Register Center, respectively. Information on antiarrhythmic drug purchases was obtained from national prescription database. Multivariable-adjusted conditional logistic regression model was used for data analysis. Compared to never-users of antiarrhythmic drugs, we found no significant association between digoxin use and prostate cancer risk overall [odds ratio (OR) 0.95, 95% confidence interval (CI): 0.89-1.01] or for advanced prostate cancer risk (OR: 0.90, 95% CI: 0.77-1.05). The result was similar also for other antiarrhythmic drugs, with the exception of sotalol, users of which had decreased risk of advanced prostate cancer (OR: 0.73, 95% CI: 0.56-0.96). Also the overall prostate cancer risk decreased by duration of sotalol use (p for trend 0.038). We show that digoxin or other common antiarrhythmic drugs generally do not associate with prostate cancer risk at population level during maximum followup of eight years. However, we cannot rule out longer term protective effects of digoxin. K1 -channel blocker sotalol shows some promise as prostate cancer preventing agent. However, findings need to be confirmed in further studies.Prostate cancer is the most common malignancy among men in most countries. 1 Despite being a major public health problem, its etiology is still not well-known. A deeper knowledge of the risk factors is needed for prevention and better treatment of the condition.Digoxin, a commonly used antiarrhythmic agent, inhibits prostate cancer cell growth by increasing apoptosis.2,3 The mechanism of action for cardiac glycosides such as digoxin involves inhibition of the plasma membrane Na1/K1-ATPase, leading to changes in intracellular K1-and Ca21-concentrations. The apoptosis-inducing effect of digoxin has been proposed to be caused by increased Ca21-uptake in prostate cancer cells, 2,3 leading to changes in activity of cyclin-dependent kinase Cdk5, p35 cleavage and p25 formation. 4 Cardiac glycosides also decrease prostate specific antigen (PSA) secretion in prostate cancer cells. 5 In a mouse model digoxin treatment caused decreased blood vessel density and inhibition of HIF-1a expression in castrationresistant xenograft tumors, but no reduction in tumor volume. 6On the other hand, digoxin possesses estrogen-mimicking effects, and its use is associated with an increased incidence of breast and uterine cancer.7 This would provide another plausible mechanism for prostate cancer inhibiting effects.Recently, a novel two-stage study confirmed, at the first stage, the cytotoxic effects of digoxin against prostate cancer cells in an in vitro cytotoxicity screen.8 ...

Digoxin and prostate cancer survival in the Finnish Randomized Study of Screening for Prostate Cancer

“…The decreased risk of advanced PCa observed among sotalol users in our previous study (Kaapu et al , 2015) did not translate into a survival benefit in the present study. Additionally, our recent cohort study (Kaapu et al , 2016) lacked this association and therefore we must consider the possible protective effects of sotalol usage in relation to prostate cancer death as uncertain.…”

“…The risk decrease was more distinct among men who had used digoxin for >10 years. We have previously demonstrated in this study population that digoxin use may be linked with a lower risk of Gleason 7–10 PCa, specifically in men under systematic PCa screening (Kaapu et al , 2015). The current study shows that this possible benefit in PCa risk does not translate into improved disease-specific survival.…”

“…Previous epidemiological studies have suggested that the antiarrhythmic drug digoxin may have prostate cancer (PCa)-protective effects especially in long-term usage (Platz et al , 2011; Wright et al , 2014; Kaapu et al , 2015). The proposed mechanism at the cellular level is digoxin-induced inhibition of the plasma membrane Na+/K+-ATPase, which elevates the intracellular Ca 2+ concentration, enhancing apoptosis of cancer cells (McConkey et al , 2000; Prevarskaya et al , 2014).…”

Using human experience to identify drug repurposing opportunities: theory and practice

“…Beta-adrenergic antagonist Cancer metastasis; cancer, breast [34] Beta-adrenergic antagonist Cancer, liver [35] Beta-adrenergic antagonist Cancer, lung [36] Beta-adrenergic antagonist Cancer, ovarian [37] Beta-adrenergic antagonist Cancer, prostate [38] Beta-adrenergic antagonist…”

Genome-wide discovery of hidden genes mediating known drug-disease association using KDDANet

“…Sotalol was normally used to treat life threatening ventricular arrhytmias and maintained normal sinus rhythm in patients with atrial fibrillation. It has been reported that sotalol was associated with decreased prostate cancer risk (Kaapu, et al, 2015). For sotalolprostate cancer association, we predicted a subnetwork consisting of 31 genes and 28 links (Fig 3a).…”